Teirahydropyridine derivatives

ABSTRACT

The present invention relates to tetrahydropyridine derivatives which have high affinity and specificity to σ receptors, whereby these compounds are thought to be effective for treatment of some psychoses.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel tetrahydropyridine derivativeswith psychotropic activities.

2. Prior Art

Antidopamine agents such as haloperidol (U.S. Pat. No. 3,438,991) areused as an antipsychotic agent. Adverse reactions in the extrapyramidaltract such as delayed dyskinesia are caused by them during long-termtherapy. Recently, safer drugs, rimcazole (JP. Pat. Publn. No.55-64,585) and BMY 148021 (GB Patent No. 2,155,925), which show highaffinity to σ receptors but low affinity to dopamine receptors, havebeen developed as psychotropic drugs. On the other hand, the existenceof a binding site of dextromethorphan (DM) in the central nervous systemhas been reported (J. Musacchio, M. Klein and L. J. Santiago, TheJournal of Pharmacology and Therapeutics 247 (2), 424 (1988), HighAffinity Dextromethorphan Binding Sites in Guinea Pig Brain; FurtherCharacterization and Allosteric Interactions). DM, which is one of themost popular antitussives, is thought to be effective for ischemicencephalopathy (F. C. Tortella, M. Pellicano and N. G. Bowery, Trips,10(12), 501 (1989), Dextromethophan and neuromodulation: old drug coughsup new activities). It is also thought that the property of σ receptors,which is labeled with [3H]3PPP adopted in the present invention,resembles that of the DM binding site (J. M. Musacchio, M. Klein and P.D. Cano 11, Life Sciences, 45, 1721 (1989), Dextromethorphan and SigmaLigands: Common Sites but Diverse Effects).

SUMMARY OF THE INVENTION

This invention relates to novel tetrahydropyridine derivatives withpsychotropic activities. Furthermore, these compounds have high affinityand specificity to σ receptors, whereby they are thought to be effectivefor some psychoses such as depression, mania, and acute and chronicschizophrenia, and cerebral ischemic disease.

DETAILED DESCRIPTION

The present invention relates to compounds of the formula: ##STR1##wherein Ar is phenyl or thienyl which may have identically ordifferently one or two substituents selected from the group consistingof lower alkyl, lower alkoxy, halogen, substituted or unsubstitutedphenyl, trifluoromethyl, and hydroxy; n is an integer of from 2 to 6; Ris hydroxy or a group of the formula: ##STR2## wherein R¹ is hydrogen orlower alkyl; R² and R³ each is hydrogen or lower alkyl or taken togetherwith the adjacent nitrogen atom may form a 5- or 6-membered heterocyclicgroup, which may be condensed with a benzene ring, where theheterocyclic group may have identically or differently have 1 to 3substituents selected from the group consisting of lower alkyl, halogen,oxo, pyrimidine, and substituted or unsubstituted phenyl; R⁴ is NH, O,or a single bond; X¹ and X² each is hydrogen, lower alkyl, halogen, orhydroxy; p and q each is an integer of 0 or 1, excluding the case wherep is 0 when q is 1, or a pharmaceutically acceptable acid addition saltthereof.

In this specification, the term "lower alkyl" refers to a straight orbranched chain C₁ to C₆ alkyl including methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, tert-pentyl, 2-methylbutyl, n-hexyl, isohexyl andthe like.

The term "lower alkoxy" refers to C₁ to C₆ alkoxy including methoxy,ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and the like.

The term "halogen" refers to fluorine, chlorine, bromine, and iodine.

"Substituted phenyl" means phenyl substituted by one or moresubstituents, of which examples are hydroxy, lower alkyl, lower alkoxy,and halogen.

The "5- or 6-membered heterocyclic group" may contain one or moreadditional heteroatoms including oxygen, sulfur, and nitrogen atoms, andexamples of the 5- or 6-membered heterocyclic group are isothiazole,pyrazole, pyridine, pyrimidine, imidazole, and isoxazole, preferably,pyrrolidine, piperidine, piperazine, imidazolidine, thiomorpholine,morpholine, pyrazolidine, and the like. The above mentioned heterocyclicgroup may be condensed with a benzene ring at any position. Further theymay have identically or differently 1 to 3 substituents selected fromthe group consisting of lower alkyl, halogen, oxo, pyrimidine, andsubstituted or unsubstituted phenyl.

Pharmaceutically acceptable acid addition salts include mineral acidsalts such as hydrochloride, sulfate, nitrate, and phosphate, andorganic acid salts such as acetate, fumarate, citrate, tartarate,maleate, and oxalate, most preferably hydrochloride, maleate andoxalate.

The compounds of this invention can be prepared by the following method.##STR3##

METHOD A Step 1

The compound (II) is reacted with the compound of the formula:

    R(CH.sub.2)nY                                              (VI)

wherein R, Y, and n each has the same meaning as defined above in anappropriate organic solvent, if necessary in the presence of a base toprepare the compound (III).

The reaction is performed at a temperature of from 50° to 200° C.,preferably from 85° to 120° C., for 1-15 hours, especially for 5-10hours.

Organic solvents which may be used are alcohols such as methanol andethanol, ethers such as diethylether and tetrahydrofuran,dimethylformamide, acetonitrile and the like, most preferablydimethylformamide.

As the base, sodium hydroxide, potassium hydroxide, calcium hydroxide,potassium carbonate, pyridine, triethylamine, and the like may be used.

Step 2

The compound (III) is subjected to dehydration in an organic solvent inthe presence of the acid to prepare the compound (Ia).

The reaction is performed at a temperature of from 0° to 120° C.,preferably at room temperature for 1-96 hours, especially for 3-72hours.

The same organic solvent as mentioned in Step 1 may be used.

The acid includes hydrochloride, acetic acid, trifluoroacetic acid andp-toluenesulfonic acid.

METHOD B Step 1

The compound (II) is reacted with the compound of the formula:

    Z.sup.1 (CH.sub.2)nY                                       (VII)

wherein Z¹, Y, and n each has the same meaning as defined above in anorganic solvent in the presence of a base to prepare the compound (IV).

The reaction is performed at 10°-150° C., preferably from roomtemperature to 110° C., for 1-20 hours, especially for 3-7 hours.

The same organic solvent and the base as mentioned Method A (step 1) maybe used.

The compound (VII) means phthalimide butylbromide,3-bromo-1-chloropropane and the like.

Step 2

The compound (IV) is reacted with the compound of the formula:

    RH                                                         (VIII)

wherein R has the same meaning as defined above in an organic solvent,if necessary in the presence of a base to prepare the compound (III).

The reaction is performed at 80°-200° C., preferably at 100°-130° C.,for 1-24 hours, especially for 2-7 hours.

The same organic solvent and the base as mentioned Step 1 may be used.

Step 3

The compound (III) is subjected to dehydration in the same manner asMethod A (step 2) to prepare the compound (Ia). Each condition is thesame as Method A (step 2).

METHOD C Step 1

The compound (II) is reacted with the compound of the formula:

    HO(CH.sub.2)nY                                             (IX)

wherein Y and n each has the same meaning as defined above, preferablyin the presence of the base to prepare the compound (IV).

The reaction is performed at 50°-200° C., preferably at 120°-150° C.,for 3-20 hours, especially for 5-9 hours.

Step 2

The compound (IV) is reacted with a chloride of a nonmetal element toprepare the compound (V).

The reaction is performed at 0°-100° C., preferably at room temperature,for 1-48 hours, especially for 2-24 hours.

The chloride includes sulfur chloride, thionylchloride, hydrochloride,carbon tetrachloride, and the like.

Step 3

The compound (V) is reacted with RH (VIII) to prepare the compound(III).

The reaction is performed at 0°-100° C., preferably from roomtemperature to 50° C. for 1-96 hours, preferably for 3-72 hours.

Step 4

The compound (III) is subjected to dehydration in the same manner asMethod A (step 2) to prepare the compound (Ia).

METHOD D Step 1

The compound (II) is reacted with N-protected-β-alanine, in the presenceof a condensing agent such as 1,3-dicyclohexylcarbodiimide, and1-hydroxybenzotriazole in an appropriate organic solvent to prepare thecompound (IV).

The reaction is performed at a temperature of from 10° to 150° C.,preferably from room temperature to 70° C., for 1-20 hours, especiallyfor 3-7 hours.

The same organic solvent as mentioned in METHOD A (Step 1) may be used.

Step 2

The compound (IV) is reacted in an appropriate solvent to remove theamino-protecting group. Then the obtained compound is subjected to areduction reaction in the presence of a reductant.

The former reaction is performed at a temperature of from 10° to 150°C., preferably from room temperature to 70° C., for 1-20 hours,especially for 3-7 hours.

The same organic solvent as mentioned in METHOD A (Step 1) may be used,most preferably trifluoroacetic acid.

The latter reduction reaction is performed in an ordinary method in thepresence of the reductant such as lithium aluminium hydride, hydroiodide, hydrogen sulfide, and sodium iodide at a temperature of from 0°to 100° C., preferably room temperature, for 1 to 7 hours, especiallyfor 2 to 4 hours.

Step 3

The compound (V) is reacted with RH (VIII) to prepare the compound (Ia).

The reaction is performed at a temperature of from 50° to 200° C.,preferably from 100° to 130° C., for 30 minutes to 5 hours, especiallyfor 1-3 hours.

The compound of the present invention can be administered orally orparenterally. For example, the compound of the present invention may beorally administered in the form of tablets, powders, capsules, andgranules, or liquid form such as syrup or elixir, and parenterally inthe form of injection of an aqueous or oily suspension.

These preparations can be prepared in a conventional manner by usingexcipients, binders, lubricants, aqueous or oily solubilizers,emulsifier, suspending agents, and the like. And further additives suchas preservatives and stabilizers can be used.

The dosages may be varied depending upon the administration route, age,weight and condition of the patient, and the kind of disease of the butis usually 5-1000 mg/day, preferably 20-200 mg/day through the oralroute, and 1-500 mg/day, preferably 5-50 mg/day through the parenteralroute in a single or divided doses.

The present invention is illustrated by the following examples andreference examples, which are not to be considered as limiting.

The abbreviations used in the examples and reference examples have thefollowing meanings.

Me: methyl,

Et: ethyl,

t-Bu: tert-butyl,

iPr: isopropyl,

Ph: phenyl,

Ts: tosyl

DMF: dimethylformamide,

aq.: aqueous.

EXAMPLE 11-[3-{4-(3,4-dichlorophenyl)-1,2,5,6-tetrahydropyridin-1-yl}-propylcarbamoyl]-2-oxopyrrolidine(Ia-1) ##STR4##

(1) A solution of 3.0 g of 4-hydroxy-4-(3,4-dichlorophenyl)piperidine(II-1) and 2.50 g of 1-{(3-chloropropyl)carbamoyl-2-oxopyrrolidine in 35ml of DMF is stirred at 105°-110° C. for 6 hours in the presence of 2.74g of NaI and 4.22 g of K₂ CO₃ (reaction condition 1). The reactionmixture is poured into ice-water, and the solution is extracted withethyl acetate. The organic layer is washed with water, dried over MgSO₄and concentrated under reduced pressure. The obtained oily substance issubjected to column chromatography with silica gel, eluting withmethylene chloride/methanol (15/1-10/1 v/v) to prepare 4.20 g of theobjective compound (III-1) as colorless needles.

mp.: 135.5°-137.0° C.

Anal Calcd. (%) for C₁₉ H₂₅ N₃ O₃ Cl₂ : C, 54.90; H, 6.10; N, 10.16; Cl,17.21. Found: C, 55.08; H, 6.08; N, 10.14; Cl, 17.11.

IR (CHCl₃): 3600, 3320, 1712, 1680, 1545, 1489, 1470.

NMR (CDCl₃) δ(200 MHz): 1.682 (dd, J₁ =12 Hz, J₂ =2 Hz, 2H); 1.772(quint, J=7 Hz, 2H); 2.042 (quint, J=8 Hz, 2H); 2.062 (s, 1H); 2.191(td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.409 (t, J=11 Hz, 2H); 2.497 (t, J=7 Hz,2H); 2.628 (t, J=8 Hz, 2H); 2.837 (dd, J₁ =11 Hz, J₂ =2 Hz, 2H); 3.394(q, J=6 Hz, 2H); 3.854 (t, J=7 Hz, 2H); 7.393, 7.401, 7.716 (sx3, 3H).

(2) A solution of 2.77 g of the compound (III-1) and 1.60 g ofp-toluenesulfonic acid in 300 ml of toluene refluxed for 48 hours toseparate water as azeotropic mixture of toluene. After removal of thesolvent, the residue is dissolved in ethyl acetate and washed withaq.NaOH and water. The solution is dried over Na₂ SO₄ and concentratedunder reduced pressure. The oily residue is subjected to columnchromatography with silica gel, eluting with ethyl acetate-methylenechloride/methanol (20/1 v/v) to prepare 2.26 g (Yield: 89.3%) of theobjective compound (Ia-1) as an oil. The maleate is recrystallized fromi-PrOH to prepare 2.50 g colorless needles. mp. 135.5°-136.5° C.

Anal Calcd. (%) for C₁₉ H₂₃ N₃ O₂ Cl₂.C₄ H₄ O₄ : C, 53.84; H, 5.32; N,8.18; Cl, 13.93. Found: C, 53.91; H, 5.31; N, 8.20; Cl, 13.84.

IR (Nujol) cm^(-1:) 3310, 1713, 1680, 1625, 1580, 1550 (sh), 1518, 1485,1455.

NMR (CDCl₃) δ(200 MHz): 1.829 (quint, J=7 Hz, 2H); 2.039 (quint, J=8 Hz,2H); 2.50˜2.55 (m, 4H); 2.612 (t, J=8 Hz, 2H); 2.714 (t, J=6 Hz, 2H);3.171 (q, J=3.3 Hz, 2H); 3.398 (q, J=7 Hz, 2H); 3.874 (t, J=7 Hz, 2H);6.100 (quint, J=2 Hz, 1H); 7.224 (dd, J₁ =8 Hz, J₂ =2 Hz, 1H); 7.397 (d,J=8 Hz, 1H); 7.463 (d, J=2 Hz, 2H); 8.513 (brs, 1H).

EXAMPLE 2-16

The reaction is performed in the same manner as Example 1 to prepare thecompound (Ia). The reaction conditions are shown in table 1 and 2, andphysical constants of the compound (III) are shown in table 3 and thoseof the compound (Ia) are shown in table 4.

                                      TABLE 1                                     __________________________________________________________________________    (Step 1)                                                                       ##STR5##                                                                     Ex. (II)              DMF K.sub.2 CO.sub.3                                                                  NaI reaction                                                                              eluent         g (%)                No. X = R(CH.sub.2).sub.n Y (VI)                                                                    (ml)                                                                              (g) (g) condition(1)                                                                          condition      compd.               __________________________________________________________________________                                                             No.                  2   CF.sub.3 (p) 2.50 g (II-2)                                                         ##STR6##     25  2.28                                                                              2.29                                                                              105-110 7 hr.                                                                         CH.sub.2 Cl.sub.2 /MeOH =                                                                    3.89 (92.2)                                                                   (III-2)              3   n-Pr(p)  2.25 g (II-3)                                                             ##STR7##     20  2.85                                                                              2.31                                                                              105 5 hr.                                                                             CH.sub.2 Cl.sub.2 /MeOH =                                                                    2.98 (74.6)                                                                   (III-3)              4   Et(p) 3.00 g (II-4)                                                                ##STR8##     30  4.04                                                                              3.28                                                                              105 7 hr.                                                                             CH.sub.2 Cl.sub.2 /MeOH =                                                                    4.10 (75.2)                                                                   (III-4)              5   Ph(p) 4.76 g (II-5)                                                                ##STR9##     57  5.19                                                                              4.22                                                                              105 24 hr.                                                                            CH.sub.2 Cl.sub.2 /MeOH = 20/1-                                               10/1           7.31 (92.3)                                                                   (III-5)              6   t-Bu(p) 6.0 g (II-6)                                                               ##STR10##    60  7.11                                                                              5.78                                                                              105 10 hr.                                                                            CH.sub.2 Cl.sub.2 /MeOH =                                                                    8.36 (81.0)                                                                   (III-6)              7   n-Pr(p) 1.95 g (II-3)                                                              ##STR11##    30  2.46                                                                              2.0 105° C. 9 hr.                                                                  CH.sub.2 Cl.sub.2 /MeOH =                                                     20/1˜10/1                                                                              2.0 (65.0)                                                                    (III-7)              8   t-Bu(p) 1.98 g (II-6)                                                              ##STR12##    20  1.35                                                                              1.10                                                                              100° C. 2.6 hr.                                                                CH.sub.2 Cl.sub.2 /MeOH =                                                     19/1-9/1       0.853 (46.9)                                                                  (III-8)              9   CF.sub.3 (p) 2.33 g (II-2)                                                         ##STR13##    30  2.62                                                                              2.14                                                                              100-105° C. 8.5                                                                CH.sub.2 Cl.sub.2 /MeOH =                                                     20/1-10/1      2.46 (65.0)                                                                   (III-9)              10  Ph 930 mg (II-5)                                                                   ##STR14##    11  1.015                                                                             0.825                                                                             105° C. 5 hr.                                                                  CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4                                               OH = 128/16/1-32/6/1                                                                        0.616 (41.0)                                                                  (III-10)             11  t-Bu(p) 844 mg (II-6)                                                              ##STR15##    11  1.00                                                                              0.813                                                                             100° C. 5.5 hr.                                                                CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4                                               OH = 128/16/1-64/8/1                                                                        0.830 (57.3)                                                                  (III-11)             12  CF.sub.3 (m) 2.5 g (II-7)                                                          ##STR16##    25  2.76                                                                              2.25                                                                              100-105° C. 5.5                                                                CH.sub.2 Cl.sub.2 /MeOH =                                                                    3.8 (90.2)                                                                    (III-12)             13  CF.sub.3 (p) 527 mg (II-2)                                                         ##STR17##     7  0.59                                                                              --  105° C. 7 hr.                                                                  CH.sub.2 Cl.sub.2 /MeOH =                                                     20/1-10/1      0.82 (86.0)                                                                   (III-13)             14  t-Bu(p) 2.03 g (II-6)                                                              ##STR18##    20  2.40                                                                              1.95                                                                              105° C. 7.5 hr.                                                                CH.sub.2 Cl.sub.2 /MeOH =                                                     20/1-7/1       2.99 (82.8)                                                                   (III-14)             15  Me(p) 1.07 g (II-8)                                                                ##STR19##    26  1.61                                                                              1.31                                                                              95° C. 7 hr.                                                                   CH.sub.2 Cl.sub.2 /MeOH =                                                     19/1-9/1       0.477 (24.8)                                                                  (III-15)             16  t-Bu(p) 980 mg (II-6)                                                              ##STR20##    20  1.16                                                                              0.94                                                                              105° C. 6.5 hr.                                                                CH.sub.2 Cl.sub.2 /MeOH =                                                     10/1-5/1       1.69 (92.6)                                                                   (III-16)             __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    (Step 2)                                                                      starting                 eluenting condition                                                                       product                                  material                                                                           acid  solvent (ml)                                                                         reflux time                                                                          (2)         (g)                                      __________________________________________________________________________    (III-2)                                                                            TsOH.H.sub.2 O                                                                      toluene (280)                                                                        48 hr. ethyl acetate-                                                                            Ia-2                                     4.24 g                                                                             (3.90 g)                                                                            dichloro-     CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                            2.26 g                                              ethane (70)                                                        (III-3)                                                                            CF.sub.3 COOH                                                                       --     10 hr. toluene/ethyl                                                                             Ia-3                                     2.52 g                                                                             (25 ml)             acetate = 1/1                                                                             2.22 g                                                            CH.sub.2 Cl.sub.2 /MeOH = 20/1                       (III-4)                                                                            CF.sub.3 COOH                                                                       --     10 hr. ethyl acetate-                                                                            Ia-4                                     4.10 g                                                                             (35 ml)             CH.sub.2 Cl.sub.2 /MeOH =                                                                 3.41 g                                                            30/1-20/1                                            (III-5)                                                                            CF.sub.3 COOH                                                                       --      9 hr. CH.sub.2 Cl.sub.2 /MeOH =                                                                 Ia-5                                     2.73 g                                                                             (30 ml)             30/1-20/1   2.40 g                                   (III-6)                                                                            CF.sub.3 COOH                                                                       --      4 hr. ethyl acetate-                                                                            Ia-6                                     2.08 g                                                                             (25 ml)             CH.sub.2 Cl.sub.2 /MeOH =                                                                 1.90 g                                                            30/1-20/1   (95.6)                                   (III-7)                                                                            CF.sub.3 COOH                                                                       --     7.5 hr.                                                                              toluene/ethyl-                                                                            Ia-7                                     2.67 g                                                                             (30 ml)             ethyl acetate = 1/1-                                                                      0.24 g                                                            ethyacetate (59.8)                                   (III-8)                                                                            CF.sub.3 COOH                                                                       --     1.8 hr.                                                                              toluene/acetone = 2/1                                                                     Ia-8                                     0.822 g                                                                             (2 ml)             CH.sub.2 Cl.sub.2 /MeOH = 9/1                                                             0.697 g                                                                       (88.8)                                   (III-9)                                                                            CF.sub.3 COOH                                                                       --     24.5 hr.                                                                             toluene/ethyl                                                                             Ia-9                                     2.27 g                                                                             (25 ml)             acetate = 1/1                                                                             1.13 g                                                            CH.sub.2 Cl.sub.2 /MeOH =                                                                 (52.1)                                                            20/1-10/1                                             (III-10)                                                                          CF.sub.3 COOH                                                                       --      1 hr. CH.sub.2 Cl.sub.2 /MeOH = 9/1                                                              Ia-10*                                  0.766 g                                                                            (10 ml)                         0.572 g                                                                       (60.5)                                    (III-11)                                                                          CF.sub.3 COOH                                                                       --      1 hr. CH.sub.2 Cl.sub.2 /MeOH = 9/1                                                              Ia-11*                                  0.914 g                                                                            (10 ml)                         0.854 g                                                                       (75.4)                                    (III-12)                                                                          CF.sub.3 COOH                                                                       --     23 hr. toluene/ethyl                                                                              Ia-12                                   3.42 g                                                                             (35 ml)             acetate = 1/1                                                                             3.15 g                                                            CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                            (96.0)                                    (III-13)                                                                          CF.sub.3 COOH                                                                       --     72 hr. toluene/ethyl                                                                              Ia-13                                   3.45 g                                                                             (45 ml)             acetate = 1/1                                                                             2.96 g                                                            CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                            (89.4)                                    (III-14)                                                                          CF.sub.3 COOH                                                                       --      5 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                             Ia-14                                   2.82 g                                                                             (35 ml)                         2.62 g                                                                        (97.0)                                    (III-15)                                                                          CF.sub.3 COOH                                                                       --      3 hr. toluene/acetone = 2/1                                                                      Ia-15                                   0.544 g                                                                             (1 ml)      (room              0.313 g                                                    temperature)       (59.6)                                    (III-16)                                                                          CF.sub.3 COOH                                                                       --      4 hr. toluene/ethyl                                                                              Ia-16                                   1.50 g                                                                             (20 ml)             acetate = 1/1                                                                             1.40 g                                                            CH.sub.2 Cl.sub.2 /MeOH =                                                                 (97.4)                                                            20/1-10/1                                            __________________________________________________________________________     *maleate                                                                 

                                      TABLE 3                                     __________________________________________________________________________    Compd.                                                                             mp. (°C.)                                                                     Anal. Calcd. (%)                                                  No.  (solvent)                                                                            Found (%) IR (cm.sup.-1)                                                                        NMR (δ)                                   __________________________________________________________________________    III-2                                                                              151.5-152.5                                                                          C.sub.20 H.sub.26 N.sub.3 O.sub.3 F.sub.3 :                                             (CHCl.sub.3)                                                                          (CDCl.sub.3)                                         (CH.sub.2 Cl.sub.2 --                                                                C, 57.92(58.10)                                                                         3600, 3310, 1713                                                                      1.712(d-d, J.sub.1 =12Hz, J.sub.2 =2Hz,                                       2H); 1.776(quintJ= 7Hz, 2H); 2.026                   Et.sub.2 O)                                                                          H, 6.26(6.34)                                                                           1680, 1605, 1510                                                                      (quint, J=7Hz, 2H); 2.046(s, 1H);                                             2.210(t-d, J.sub.1 =13Hz, J.sub.2 =4Hz,                                       2H);                                                        N, 10.15(10.16)                                                                         1489    2.432(t-d, J.sub.1 =11Hz, J.sub.2 =2Hz, 2H;                                   2.490(t, J=7Hz, 2H); 2.601                                  F, 13.57(13.79)   (t, J=8Hz, 2H); 2.838(d-d J.sub.1 =11Hz,                                      J.sub.2 =2Hz, 2H); 7.595(d, J=8Hz,                                            2H); 7.679(d, J=8Hz, 2H); 8.619(brs, 1H)        III-3                                                                              96.0-97.0                                                                            C.sub.22 H.sub.33 N.sub.3 O.sub.3 :                                                     (CHCl.sub.3)                                                                          (CDCl.sub.3)                                         (ethyl-                                                                              C, 67.84(68.18)                                                                         3600, 3320, 1713                                                                      1.634(sextet, J=7Hz, 2H);                                                     1.70˜1.85(m, 4H); 2.018(quint,                                          J=8Hz,                                               acetate-                                                                             H, 8.41(8.58)                                                                           1680, 1602, 1547                                                                      2H); 2.185(t-d, J.sub.1 =13Hz, J.sub.2                                        =4Hz, 2H); 2.38˜ 2.64(m, 8H); 7.160            Et.sub.2 O                                                                           N, 10.74(10.84)                                                                         1490, 1460                                                                            (d, J=8Hz, 2H); 7.343(d, J=8Hz, 2H);                                          8.551(brs, 1H)                                  III-4                                                                              84.0-85.5        (CHCl.sub.3)                                                                          (CDCl.sub.3)                                                          3600, 3320, 1713                                                                      1.235(t, J=8Hz, 3H); 1.72˜1.83(m,                                       4H); 2.022(quint, J=7Hz, 2H);                                         1680, 1545                                                                            2.191(t-d, J.sub.1 =13Hz, J.sub.2 =4Hz,                                       2H); 2.4˜2.7(m, 8H); 2.819(d-d,                                         J.sub.1 =                                                                     12Hz, J.sub.2 =1Hz, 2H); 3.375(q, J=6Hz,                                      2H); 3.848(t, J=7Hz, 2H); 7.186                                               (d, J=8Hz, 2H); 7.442(d, J=8Hz, 2H);                                          8.555(brs, 1H)                                  III-5                                                                              155.5-156.5                                                                          C.sub.25 H.sub.31 N.sub.3 O.sub.3.                                                      (CHCl.sub.3)                                                                          (CDCl.sub.3)                                         (CH.sub.2 Cl.sub.2 --                                                                1/5H.sub.2 O                                                                            3600, 3320, 1713                                                                      1.84˜1.73(m, 4H); 2.014(quint, J=8Hz,                                   2H); 2.247(t-d, J.sub.1 =14Hz,                       Et.sub.2 O)                                                                          C, 70.50(70.63)                                                                         1682, 1545                                                                            J.sub.2 =4Hz, 2H); 2.458(t-d, J.sub.1                                         =14Hz, J.sub.2 =1H, 2H); 2.507(t, J=7Hz,                                      2H);                                                        H, 7.46(7.82)     2.595(t, J=8Hz, 2H); 2.853(d, J=11Hz, 2H);                                    3.386(q, J=6Hz,                                             N, 9.65(9.88)     2H); 3.846(t, J=7Hz, 2H);                                                     7.25˜7.65(m, 9H); 8.577 (brs, 1H)         III-6                                                                              149.5-150.5                                                                          C.sub.23 H.sub.35 N.sub.3 O.sub.3                                                       (CHCl.sub.3)                                                                          (CDCl.sub.3)                                         (CH.sub.2 Cl.sub.2 --                                                                C, 68.48(68.80)                                                                         3600, 3320, 1713                                                                      1.303(s, 9H); 1.521(s, 1H); 1.738(d-d,                                        J.sub.1 =11Hz, J.sub.2 =3Hz, 2H;                     Et.sub.2 O)                                                                          H, 8.69(8.79)                                                                           1680, 1543                                                                            1.793(quint, J=8Hz, 2H); 2.022(quint,                                         J=7Hz, 2H); 2.195(t-d, J.sub.1 =                            N, 10.39(10.46)   13Hz, J.sub.2 =4Hz, 2H); 2.39˜2.53(m,                                   4H); 2.593(t, J=8Hz, 2H); 2.823                                               (d, J=11Hz, 2H); 3.375(q, J=7Hz, 2H);                                         3.851(t, J=7Hz, 2H); 7.38,                                                    7.43(ABq, J=9Hz, 4H); 8.543(brs, 1H)            III-7                                                                              161.0˜162.5                                                                    C.sub.22 H.sub.33 N.sub.2 O.sub.3 Cl.                                                   (Nujol) (CDCl.sub.3)                                         (CH.sub.2 Cl.sub.2 --                                                                1/3H.sub.2 O                                                                            3310, 2640, 2560                                                                      0.939(t, J=7Hz, 3H); 1.630(sextet, J=7Hz,                                     2H); 1.781(d, J=12Hz,                                ethyl- C, 63.46(63.68)                                                                         1730, 1680                                                                            2H); 1.87-2.10(m, 4H); 2.246(t-d, J.sub.1                                     =12Hz, J.sub.2 =3Hz, 2H); 2.50-                      acetate)                                                                             H, 8.02(8.18)     2.68(m, 8H); 2.920(d, J=12Hz, 2H); 2.957(t,                                   J=7Hz, 2H); 3.804                                           H, 6.83(6.75)     (t, J=7Hz, 2H); 7.156, 7.406(ABq, J=8Hz,                                      4H)                                                         F, 7.98(8.54)                                                     III-8                                                                              207.0-210.0                                                                          C.sub.23 H.sub.34 N.sub.2 O.sub.3 :                                                     (CHCl.sub.3)                                                                          (CDCl.sub.3)                                         (CH.sub.2 Cl.sub.2 --                                                                C, 63.73(71.47)                                                                         3663, 3598, 3345                                                                      1.299(s, 9H); 1.960(d, J= 14Hz, 2H);                                          1.95-2.13(m, 4H); 2.17-2.35                          Et.sub.2 O-                                                                          H, 8.09(8.87)                                                                           2630, 2460, 2410                                                                      (m, 2H); 2.606(t, J=8Hz, 2H); 2.694(t-d,                                      J.sub.1 =14Hz, J.sub.2 =2Hz, 2H);                    n-hexane)                                                                            N, 7.31(7.25)                                                                           1740, 1692, 1611                                                                      2.95-3.10(m, 4H); 3.25-3.45(m, 4H);                                           3.800(t, J=7Hz, 2H); 7.368,                                           1509, 1471, 1460                                                                      7.441(ABq, J=8Hz, 4H)                           III-9                                                                              147.0˜148.0                                                                    C.sub.26 H.sub.25 N.sub.2 O.sub.3 F.sub.3.                                              (CHCl.sub.3)                                                                          (CDCl.sub.3)                                         (CH.sub.2 Cl.sub.2 --                                                                1/5H.sub.2 O                                                                            3600, 1738, 1693                                                                      1.715(d-d, J.sub.1 =14Hz, J.sub.2 =2Hz,                                       2H); 1.878(s, 1H); 1.898(quint, J=8                  Et.sub.2 O)                                                                          C, 59.79(59.75)                                                                         1620    Hz, 2H); 2.021(quint, J=8Hz, 2H);                                             2.152(t-d, J.sub.1 =14Hz, J.sub.2 =4Hz,                                       2H);                                                        H, 6.27(6.97)     2.451(t-d, J.sub.1 =15Hz, J.sub.2 =2Hz,                                       2H); 2.482(t, J=8Hz, 2H); 2.584                             N, 6.79(6.37)     (t, J=8Hz, 2H); 2.862(d, J=15Hz, 2H);                                         2.936(t, J=7Hz, 2H); 3.794                                  F, 14.26(14.18)   (t, J=7Hz, 2H); 7.579, 7.627(ABq, J=8Hz,                                      4H)                                             III-10                                                                             225.0˜228.0                                                                    C.sub.25 H.sub.33 N.sub.3 O.sub.2.                                                      (Nujol) (CDCl.sub.3)                                         (CH.sub.2 Cl.sub.2 --                                                                1/10H.sub.2 O                                                                           3300, 3055, 3030                                                                      1.775(quint, J=7Hz, 2H); 1.845(d, J=14Hz,                                     2H); 1.89-1.96(m, 4H);                               MeOH-- C, 73.25(73.35)                                                                         2810, 2770, 2670                                                                      2.171(t-d, J.sub.1 =13Hz, J.sub.2 =4Hz,                                       2H); 2.52-2.63(m, 4H); 2.900(d,                      Et.sub.2 O)                                                                          H, 8.26(8.18)                                                                           1606, 1528, 1487                                                                      J=12Hz, 2H); 3.25-3.38(m, 4H); 7.30-7.70(m,                                   9H)                                                         N, 10.21(10.27)                                                                         1471, 1456, 1448                                        III-11                                                                             138.5˜140.5                                                                    C.sub.23 H.sub.37 N.sub.3 O.sub.2.                                                      (Nujol) (CDCl.sub.3)                                         (CH.sub.2 Cl.sub.2 --                                                                2/5H.sub.2 O                                                                            3350, 3150, 1631                                                                      1.322(s, 9H); 1.76-1.94(m, 8H); 2.262(t-d,                                    J.sub.1 =14Hz, J.sub.2 =4Hz, 2H);                    Et.sub.2 O)                                                                          C, 70.07(69.98)                                                                         1542, 1509, 1485                                                                      2.50-2.65(m, 4H); 2.951(d, J=11Hz, 2H);                                       3.30-3.39(m, 4H);                                           H, 9.54(9.65)                                                                           1460, 1441, 1388                                                                      5.738(brs, 1H); 7.378, 7.418(ABq, J=8Hz,                                      4H)                                                         N, 10.66(10.64)                                                   III-12                                                                             113.5˜114.5                                                                    C.sub.20 H.sub.26 N.sub.3 O.sub.3 F.sub.3 :                                             (CHCl.sub.3)                                                                          (CDCl.sub.3)                                         (CH.sub.2 Cl.sub.2 --                                                                C, 57.90(58.10)                                                                         3600, 3320, 1713                                                                      1.715(d-d, J.sub.1 =12Hz, J.sub.2 =2Hz,                                       2H); 1.780(quintJ=7Hz, 2H); 2.000                    Et.sub.2 O)                                                                          H, 6.26(6.34)                                                                           1680, 1545, 1490                                                                      (s, 1H); 2.027(quint, J=7Hz, 2H);                                             2.253(t-d, J.sub.1 =13Hz, J.sub.2 =4Hz,                                       2H);                                                        N, 10.14(10.16)                                                                         1385, 1332                                                                            2.442(d, J=12Hz, 2H); 2.504(t, J=7Hz, 2H);                                    2.606(t, J=8Hz, 2                                           F, 13.49(13.79)   H); 2.854(d-d, J.sub.1 =11Hz, J.sub.2 =3Hz,                                   2H); 3.394(quint, J=7Hz, 2H);                                                 3.850(t, J=7Hz, 2H); 7.474(d, J=7Hz, 1H);                                     7.492(t, J=7Hz, 1H);                                                          7.746(d, J=7Hz, 1H); 7.871(s, 1H);                                            8.678(brs, 1H)                                  III-13                                                                             oil    --        --      (CDCl.sub.3)                                                                  1.30-1.44(m, 2H); 1.584(quint×2,                                        J=7Hz, 4H); 1.747(d, J=12Hz, 2H);                                             2.022(quint, J=7Hz, 2H); 2.216(t-d, J.sub.1                                   =13Hz, J.sub.2 =4Hz, 2H);                                                     2.41-2.49(m, 4H); 2.600(t, J=8Hz, 2H);                                        2.773(d, J=11Hz, 2H); 3.292                                                   (q, J=7Hz, 2H); 3.837(t, J=7Hz, 2H); 7.598,                                   7.662(ABq, J=9                                                                Hz, 4H); 8.428(brs, 1H)                         III-14                                                                             153.0˜154.0                                                                    C.sub.24 H.sub.37 N.sub.3 O.sub.3 :                                                     (CHCl.sub.3)                                                                          (CDCl.sub.3)                                         (CH.sub.2 Cl.sub.2 --                                                                C, 69.29(69.36)                                                                         3600, 3280, 1702                                                                      1.319(s, 9H); 1.623(s, 1H); 1.71-1.86(m,                                      8H); 2.190(t-d, J.sub.1 =13                          Et.sub.2 O)                                                                          H, 8.93(8.97)                                                                           (sh), 1697, 1645                                                                      Hz, J.sub.2 =4Hz, 2H); 2.39-2.58(m, 6H);                                      2.824(d, J=11Hz, 2H); 3.375                                 N, 10.14(10.11)                                                                         1530, 1480, 1460                                                                      (q, J=7Hz, 2H); 3.75-3.82(m, 2H); 7.463,                                      7.372(ABq, J=9Hz, 4H);                                                1400    9.479(brs, 1H)                                  III-15                                                                             ˜180                                                                           --        --      (CDCl.sub.3)                                         (CH.sub.2 Cl.sub.2 --    1.782(d-d, J.sub.1 =14Hz, J.sub.2 =2Hz,                                       2H); 1.90-2.12(m, 6H); 2.275(t-d,                    Et.sub.2 O)              J.sub.1 =14Hz, J.sub.2 =2Hz, 2H); 2.330(s,                                    3H); 2.600(t, J=8Hz, 4H); 2.965                                               (t, J=7Hz, 4H); 3.810(t, J=7Hz, 2H); 7.163,                                   7.394(ABq, J=8Hz, 4H)                           III-16                                                                             129.0˜130.5                                                                    C.sub.28 H.sub.41 N.sub.3 O.                                                            (CHCl.sub.3)                                                                          (CDCl.sub.3)                                         (CH.sub.2 Cl.sub.2 --                                                                1/3H.sub.2 O                                                                            3600, 1602, 1580                                                                      1.661(s, 1H); 1.77-1.94(m, 4H); 2.285(t-d,                                    J.sub.1 =13Hz, J.sub.2 =2Hz, 2H);                    Et.sub.2 O)                                                                          C, 76.08(76.15)                                                                         1505(sh), 1495,                                                                       2.460(t, J=7Hz, 2H); 2.53-2.65(m, 6H);                                        3.18-3.24(m, 2H);                                           H, 9.41(9.51)                                                                           1470, 1460(sh),                                                                       6.80-7.48(m, 9H)                                            N, 9.63(9.51)                                                                           1455, 1400, 1380                                        __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    Compd.                                                                             mp. (°C.)                                                                       Anal Calcd. (%)                                                 No.  (solvent)                                                                              Found (%)      IR (cm.sup.-1)                                                                        NMR (δ)                            __________________________________________________________________________    Ia-2 187.0-188.5                                                                            C.sub.20 H.sub.24 N.sub.3 O.sub.2 F.sub.3.C.sub.2 H.sub.2                     O.sub.4        (CHCl.sub.3)                                                                          (CDCl.sub.3 --CD.sub.3 OD= 1/5)               (oxalate)                                                                              C, 54.45 (54.43)                                                                             3290, 2600 (br),                                                                      2.00˜2.20(m, 4H); 2.620(t,                                              J=8Hz, 2H); 2.98˜2.87(brs,              (i-PrOH) H, 5.38 (5.40) 1710, 1685, 1615                                                                      2H); 3.292(t, J=8Hz, 2H); 3.451(t,                                            J=7Hz, 2H); 3.556(t,                                   N, 8.76 (8.66) 1550, 1460                                                                            J=6Hz, 2H); 3.819(t, J=7Hz, 2H);                                              3.977(d, J=3Hz,                                        F, 12.26 (11.74)       2H); 6.239(t, J=3Hz, 1H); 7.646(s,                                            4H)                                      Ia-3 162.0-162.5                                                                            C.sub.26 H.sub.35 N.sub.3 O.sub.6 :                                                          (Nujol) (CDCl.sub.3)                                  (maleate)                                                                              C, 64.23 (64.31)                                                                             3330, 1705 (s),                                                                       0.935(t, J=7Hz, 3H); 1.629(sextet,                                            J=7Hz, 2H);                                   (i-PrOH) H, 7.23 (7.27) 1695, 1620, 1575                                                                      1.828(quint, J=7Hz, 2H);                                                      2.015(quint, J=7Hz, 2H);                               N, 8.54 (8.65) 1528    2.49˜2.64(m, 8H); 2.706(t,                                              J=6Hz, 2H); 3.158(q,                                                          J=3Hz, 2H); 3.387(q, J=7Hz, 2H);                                              3.858(t, J=7Hz,                                                               2H); 6.032(quint, J=2Hz, 1H);                                                 7.117(d, J=8Hz, 2H);                                                          7.302(d, J=8Hz, 2H); 8.486(brs, 1H)      Ia-4 86.0-87.0                                                                              C.sub.21 H.sub.29 N.sub.3 O.sub.2                                                            (CHCl.sub.3)                                                                          (CDCl.sub.3)                                  (ether)  C, 70.97 (70.95)                                                                             3220, 1713, 1682                                                                      1.227(t, J=7Hz, 3H); 1.824(quint,                                             J=7Hz, 2H);                                            H, 8.11 (8.22) 1545, 1488, 1460                                                                      2.015(quint, J=7Hz, 2H); 2.527(t,                                             J=8Hz, 2H);                                            N, 11.97 (11.82)       2.561(brs, 2H); 2.591(t, J=8Hz, 2H);                                          2.629(q, J=8Hz,                                                               2H); 3.150(q, J=3Hz, 2H); 3.386(q,                                            J=7Hz, 2H);                                                                   3.856(t, J=7Hz, 2H); 6.017(quint,                                             J=2Hz, 1H); 7.141(d,                                                          J=8Hz, 2H); 7.310(d, J=8Hz, 2H);                                              8.490(brs, 1H)                           Ia-5 144.0-146.0                                                                            C.sub.25 H.sub.29 N.sub.3 O.sub.2                                                            (CHCl.sub.3)                                                                          (CDCl.sub.3)                                  (decom. point)                                                                         C, 74.32 (74.41)                                                                             3320, 1702, 1680                                                                      1.840(quint, J=7Hz, 2H);                                                      2.019(quint, J=8Hz, 2H);                      (ethyl acetate)                                                                        H, 7.21 (7.24) 1600, 1545, 1485                                                                      2.555(t, J=8Hz, 2H); 2.584(br, 2H);                                           2.596(t, J=8Hz,                                        N, 10.49 (10.41)       2H); 2.733(t, J=6Hz, 2H); 3.190(q,                                            J=3Hz, 2H);                                                                   3.398(q, J=7Hz, 2H); 3.863(t, J=7Hz,                                          2H); 6.128(quint,                                                             J=3Hz, 1H); 7.26˜7.63(m, 9H);                                           8.504(brs, 1H)                           Ia-6 173.0-174.0                                                                            C.sub.23 H.sub.33 N.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4                                    (NUjol) (CDCl.sub.3)(free)                            (decom.) C, 64.68 (64.91)                                                                             3320, 1712, 1690                                                                      1.314(s, 9H); 1.837(quint, J=7Hz,                                             2H); 2.022(quint,                             (maleate)                                                                              H, 7.48 (7.46) 1620, 1580, 1543                                                                      J=7Hz, 2H); 2.5˜2.6(m, 6H);                                             2.717(t, J=6Hz, 2H);                          (i-PrOH--MeOH)                                                                         N, 8.38 (8.41)         3.169(q, J=3Hz, 2H); 3.387(q, J=6Hz,                                          2H); 6.023(q,                                                                 J=2Hz, 1H); 7.332(s, 4H); 8.496(brs,                                          1H)                                      Ia-7 190.0-191.0                                                                            C.sub.20 H.sub.24 N.sub.3 O.sub.2 F.sub.3.C.sub.2 H.sub.2                     O.sub.4        (Nujol) (CDCl.sub.3)                                  (oxalate)                                                                              C, 64.39 (64.85)                                                                             2500, 1732, 1725                                                                      0.935(t, J=7Hz, 3H); 1.629(sextet,                                            J=8Hz, 2H);                                   (MeOH)   H, 7.27 (7.26) (sh), 1685, 1610                                                                      1.978(sextet, J=7Hz, 2H);                                                     1.989(sextet, J=7Hz, 2H);                              N, 6.12 (6.30) (br)    2.52-2.60(m, 8H); 2.745(t, J=6Hz,                                             2H); 2.973(t, J=7Hz,                                                          2H); 3.195(q, J=3Hz, 2H); 3.795(t,                                            J=7Hz, 2H);                                                                   6.022(quint, J=2Hz, 1H); 7.120,                                               7.299(ABq, J=8Hz,                                                             4H)                                      Ia-8 96.0-97.0                                                                              C.sub.23 H.sub.32 N.sub.2 O.sub.2 :                                                          (CHCl.sub.3)                                                                          (CDCl.sub.3)                                  (Et.sub.2 O-n-hexane)                                                                  C, 75.23 (74.96)                                                                             1737, 1692, 1508                                                                      1.317(s, 9H); 1.962(sextet, J=6Hz,                                            2H); 1.996(sextet,                                     H, 8.73 (8.75) 1482, 1459, 1427                                                                      J=6Hz, 2H); 2.570(q, J=8Hz, 6H);                                              2.721(t, J=5Hz,                                        N, 7.65 (7.60) 1364    2H); 2.972(t, J=7Hz, 2H); 3.174(q,                                            J=3Hz, 2H);                                                                   3.801(t, J=7Hz, 2H); 6.031(quint,                                             J=2Hz, 1H); 7.331(s,                                                          4H)                                      Ia-9 149.5-150.5                                                                            C.sub.20 H.sub.23 N.sub.2 O.sub.2 F.sub.3                                                    (CHCl.sub.3)                                                                          (CDCl.sub.3)                                  (CH.sub.2 Cl.sub.2 --Et.sub.2 O)                                                       C, 63.17 (63.15)                                                                             1738, 1692, 1615                                                                      1.964(sextet, J=7Hz, 2H);                                                     2.001(sextet, J=7Hz, 2H);                              H, 6.09 (6.09) 1477, 1365, 1325                                                                      2.538(q, J=8Hz, 6H); 2.745(t, J=6Hz,                                          2H); 2.980(t,                                          N, 7.38 (7.36)         J=7Hz, 2H); 3.207(q, J=3Hz, 2H);                                              3.803(t, J=7Hz,                                        F, 15.06 (14.98)       2H); 6.160(quint, J=3Hz, 1H); 7.472,                                          7.565(ABq,                                                                    J=8Hz, 4H)                               Ia-10                                                                              164.0-166.0                                                                            C.sub.25 H.sub.31 N.sub.3 O.C.sub.4 H.sub.                                                   (Nujol).4                                                                             (CD.sub.3 OD)                                 (malenate)                                                                             C, 68.89 (68.89)                                                                             3403, 3037, 2330                                                                      1.88-2.06(m, 4H); 2.951(brs, 2H);                                             3.20-3.40(m, 6H);                             (MeOH--Et.sub.2 O)                                                                     H, 6.97 (6.98) 1700, 1640, 1578                                                                      3.557(brs, 2H); 3.959(brs, 2H);                                               6.220(s, 1H); 6.248(s,                                 N, 8.30 (8.31) 1537, 1498, 1457                                                                      2H); 7.30-7.70(m, 9H)                    Ia-11                                                                              138.0-140.0                                                                            C.sub.23 H.sub.35 N.sub.3 O.C.sub.4 H.sub.4 O.sub.4.1/5H.sub                  .2 O           (Nujol) (CD.sub.3 OD)                                 (malenate)                                                                             C, 66.16 (66.29)                                                                             3522, 3362, 2718                                                                      1.316(s, 9H); 1.87-2.08(m, 6H);                                               2.896(brs, 2H);                               (MeOH--Et.sub.2 O)                                                                     H, 8.21 (8.12) 2350, 1701, 1630                                                                      3.22-3.36(m, 8H); 3.526(brs, 2H);                                             3.918(brs, 2H);                                        N, 8.82 (8.59) 1579, 1524, 1498                                                                      6.117(quint, J=3Hz, 1H); 6.245(s,                                             2H); 7.414(s, 4H)                        Ia-12                                                                              128.0-129.0                                                                            C.sub.20 H.sub.24 N.sub.3 O.sub.2 F.sub.3.C.sub.4 H.sub.4                     O.sub.4        (Nujol) (CDCl.sub.3)                                  (malenate)                                                                             C, 56.35 (56.36)                                                                             3300, 2300 (br),                                                                      1.831(quint, J=7Hz, 2H);                                                      2.027(quint, J=8Hz, 2H);                      (i-PrOH--MeOH)                                                                         H, 5.55 (5.52) 1710, 1638, 1625                                                                      2.51-2.65(m, 6H); 2.729(t, J=6Hz,                                             2H); 3.186(q,                                          N, 8.21 (8.22) 1570, 1530, 1500                                                                      J=3Hz, 2H); 3.397(q, J=7Hz, 2H);                                              3.865(t, J=7Hz,                                        F, 11.08 (11.14)                                                                             1460, 1445                                                                            2H); 6.145(quint, J=2Hz, 1H);                                                 7.41-7.63(m, 4H);                                                             8.517(brs, 1H)                           Ia-13                                                                              128.0-129.5                                                                            C.sub.22 H.sub.28 N.sub.3 O.sub.2 F.sub.3.C.sub.2 H.sub.2                     O.sub.4.1/2PrOH                                                                              (Nujol) (CDCl.sub.3)                                  (oxalate)                                                                              C, 56.18 (56.35)                                                                             3510, 3310, 1708                                                                      1.35-1.47(m, 2H); 1.613(quint×2                                         , J=7Hz, 4H);                                 (MeOH-i-PrOH)                                                                          H, 6.23 (6.39) 1690, 1680, 1615                                                                      2.025(quint, J=8Hz, 2H);                                                      2.44-2.65(m, 6H);                                      N, 7.70 (7.73) 1537, 1480, 1460                                                                      2.716(t, J=5Hz, 2H); 3.181(q, J=3Hz,                                          2H); 3.312(q,                                          F, 10.22 (10.49)       J=6Hz, 2H); 3.862(t, J=7Hz, 2H);                                              6.157(quint, J=2Hz,                                                           1H); 7.472, 7.563(ABq, J=8Hz, 4H);                                            8.419(brs, 1H)                           Ia-14                                                                              185.0-186.5                                                                            C.sub.24 H.sub.35 N.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4                                    (Nujol) (CDCl.sub.3)                                  (malenate)                                                                             C, 65.53 (65.48)                                                                             3285, 1695, 1648                                                                      1.312(s, 9H); 1.77-1.88(m, 6H);                                               2.49-2.56(m, 6H);                             (MeOH)   H, 7.62 (7.65) 1620, 1580, 1523                                                                      2.704(t, J=6Hz, 2H); 3.160(q, J=3Hz,                                          2H); 3.380(q,                                          N, 8.24 (8.18) 1477, 1460, 1450                                                                      J=7Hz, 2H); 3.75-3.82(m, 2H);                                                 6.026(quint, J=2Hz,                                                           1H); 7.328(s, 4H); 9.444(brs, 1H)        Ia-15                                                                              109.5-110.0                                                                            C.sub.20 H.sub.26 N.sub.2 O.sub.2                                                            (CHCl.sub.3)                                                                          (CDCl.sub.3)                                  (Et.sub.2 O-n-hexane)                                                                  C, 73.79 (73.59)                                                                             1738, 1692, 1512                                                                      1.939(quint, J=7Hz, 2H);                                                      2.007(quint, J=7Hz, 2H);                               H, 8.08 (8.03) 1485, 1460, 1430                                                                      2.328(s, 3H); 2.49-2.63(m, 4H);                                               2.713(t, J=5Hz, 2H);                                   N, 8.55 (8.58) 1367    2.969(t, J=7Hz, 2H); 3.153(q, J=3Hz,                                          2H); 3.794(t,                                                                 J=7Hz, 2H); 6.018(quint, J=2Hz, 1H);                                          7.115,                                                                        7.280(ABq, J=8Hz, 4H)                    Ia-16                                                                              105.0-106.0                                                                            C.sub.28 H.sub.39 N.sub.3 O.sub.2.C.sub.4 H.sub.4 O.sub.4                                    (Nujol) (CDCl.sub.3)                                  (malenate)                                                                             C, 66.49 (66.54)                                                                             1710, 1622, 1598                                                                      1.315(s, 9H); 1.78-1.84(m, 8H);                                               2.43-2.75(m, 8H);                             (i-PrOH--Et.sub.2 O)                                                                   H, 7.26 (7.29) 1575, 1495(sh),                                                                       3.16-3.25(m, 6H); 6.043(quint,                                                J=2Hz, 1H);                                   210.0-212.5                                                                            N, 6.59 (6.47) 1480, 1462, 1450                                                                      6.80-7.34(m, 9H)                              (MeOH)                  1385, 1360                                       __________________________________________________________________________

EXAMPLE 171-[4-{4-(4-trifluoromethylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}-butylcarbamoyl]-2-oxopyrrolidine(Ia-17) ##STR21##

(1) A solution of 2.00 g of4-hydroxy-4-(4-trifluoromethylphenyl)piperidine (II-2) and 2.42 g ofphthalimido butyl bromide in 20 ml of DMF in the presence of 2.26 g ofK₂ CO₃ is stirred at 105° C. for 6 hours. The reaction mixture is pouredinto ice-water, and the solution is extracted with ethyl acetate. Theorganic layer is washed with water, dried over Na₂ SO₄ and concentratedunder reduced pressure. The obtained residue is subjected to columnchromatography with silica gel, eluting with methylene chloride/methanol(20/1 v/v). The purified substance is recrystallized from methylenechloride/ether to prepare 3.0 g of the compound (IV-1). mp.139.0°-140.5° C.

Anal Calcd. (%) for C₂₄ H₂₅ N₂ O₃ F₃ : C, 64.23; H, 5.73; N, 6.10; F,12.98. Found: C, 64.57; H, 5.64; N, 6.27; F, 12.77.

IR (CHCl₃): 3590, 1772, 1713, 1618, 1470, 1440, 1409(sh), 1389.

NMR (CDCl₃) (200 MHz) δ:1.52-1.80 (m, 6H); 1.843 (s, 1H); 2.152 (td, J₁=13 Hz, J₂ =4 Hz, 2H); 2.37-2.50 (m, 4H); 2.838 (dd, J₁ =9 Hz, J₂ =2 Hz,2H); 3.728 (t, J=7 Hz, 2H); 7.613, 7.640 (ABq, J=9 Hz, 4H) 7.7-7.9 (m,4H).

(2) A solution of 2.56 g of the compound (IV-1) and 424 mg of hydrazinehydrate in 25 ml of ethanol is refluxed for 3 hours. After the excessagent is distilled off under reduced pressure, the residue is mixed with1.15 g of 1-phenoxycarbonyl-2-oxopyrrolidine and heated at 105° C. for1.5 hours. The reaction mixture is subjected to column chromatographywith silica gel, eluting with methylene chloride/methanol=20/1-10/1 v/v.The obtained material is recrystallized from methylene chloride-ether toprepare 1.76 g (Yield: 73.5%) of the objective compound (III-17) ascolorless needles. mp. 150.5°-152.0° C.

Anal Calcd. (%) for C₂₁ H₂₈ N₃ O₃ F₃ : C, 58.78; H, 6.51; N, 9.75; F,13.56. Found: C, 59.01; H, 6.60; N, 9.83; F, 13.33.

IR (CHCl₃): 3590, 3320, 1713, 1680, 1618, 1545, 1489, 1460, 1409, 1385,1328.

NMR (CDCl₃): 1.57-1.63 (m, 4H); 1.743 (d, J=12 Hz, 2H); 2.019 (quint,J=7 Hz, 2H); 2.189 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.341 (s, 1H);2.42-2.55 (m, 4H); 2.595 (t, J=8 Hz, 2H); 2.862 (dd, J₁ =10 Hz, J₂ =2Hz, 2H); 3.311 (q, J=6 Hz, 2H); 3.822 (t, J=7 Hz, 2H); 7.591, 7.653(ABq, J=9 Hz, 4H); 8.438 (brs, 1H)

(3) A solution of 1.40 g of the compound (III-17) in 20 ml of trifluoroacetic acid is refluxed for 72 hours. After removal of the excessreagent, the residue is poured into sodium hydroxide, and the solutionis extracted with ethyl acetate. The organic layer is dried over MgSO₄and concentrated under reduced pressure. The oily residue is subjectedto column chromatography with silica gel, eluting with methylenechloride/methanol (20/1 v/v) and recrystallized from i-PrOH-ether toprepare 1.31 g (Yield: 97.7%) of the objective compound (Ia-17) asneedles.

mp. 136.0°-136.5° C.

Anal Calcd. (%) for C₂₁ H₂₆ N₃ O₂ F₃ : C, 61.87; H, 6.49; N, 10.26; F,13.87. Found: C, 61.60; H, 6.40; N, 10.26; F, 13.92.

IR (CHCl₃): 3310, 1713, 1680, 1615, 1545, 1487, 1458, 1385, 1327.

NMR (CDCl₃) (200 MHz) δ:1.55-1.67 (m, 4H); 2.031 (quint, J=8 Hz, 2H);2.47-2.65 (m, 6H); 2.725 (t, J=5 Hz, 2H); 3.190 (q, J=3 Hz, 2H); 3.344(q, J=6 Hz, 2H); 3.857 (t, J=8 Hz, 2H); 6.154 (quint, J=2 Hz, 1H);7.471, 7.564 (ABq, J=8 Hz, 4H); 8.436 (brs, 1H).

EXAMPLE 181-[N-propyl-N-[3-{4-(4-t-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}-propylcarbamoyl]]-2-oxopyrrolidine(Ia-18) ##STR22##

(1) A solution of 2.00 g of the compound (II-6) and 1.42 g of3-bromo-1-chloropropane in 30 ml of DMF is stirred in the presence of2.37 g of K₂ CO₃ at room temperature for 3.5 hours. The reaction mixtureis poured into ice-water, and the solution is extracted with ethylacetate. The organic layer is washed with water, dried and concentratedunder reduced pressure to prepare 1.32 g of the compound (IV-2).

(2) A solution of 0.5 g of the compound (IV-2) and 0.44 ml of n-propylin 1 ml of DMF is heated at 105° C. for 2 hours under stirring. Themixture is concentrated, and the residue is poured into aq.NaOH. Thesolution is extracted with methylene chloride, the organic layer isdried over MgSO₄ under reduced pressure. The oily residue is mixed with310 mg of 1-phenoxycarbonyl-2-oxopyrrolidine and reacted at 115° C. for2 hours. The reaction mixture is dissolved into methylene chloride,washed with aq.NaOH and aq.NaCl in order, dried over Na₂ SO₄, andconcentrated under reduced pressure. The oily residue is subjected tocolumn chromatography with silica gel, eluting with methylenechloride/methanol (20/1-10/1 v/v) to prepare 500 mg (Yield: 70.0%) ofthe compound (III-18) as an oil.

IR (CHCl₃): 3595, 1720, 1665, 1605, 1517, 1465(sh), 1460, 1425, 1400,1375.

NMR (CDCl₃): 0.889 (t, J=7 Hz, 3H); 1.316 (s, 9H); 1.594 (q, J=8 Hz,2H); 1.74-1.89 (m, 4H); 2.076 (quint, J=7 Hz, 2H); 2.207 (t, J=15 Hz,2H); 2.435 (t, J=8 Hz, 2H); 2.48-2.60 (m, 4H); 2.80-2.90 (m, 2H); 3.317(t, J=4 Hz, 2H); 3.421 (t, J=4 Hz, 2H); 3.712 (t, J=7 Hz, 2H); 7.368,7.436 (ABq, J=8 Hz, 4H)

(3) A solution of 1.40 g of the compound (III-17) in 15 ml oftrifluoroacetic acid is refluxed for 2.5 hours. The solution isconcentrated, and the residue is poured into aq.NaOH. The solution isextracted with ethyl acetate, and the organic layer is dried over MgSO₄and concentrated under reduced pressure. The oily residue is subjectedto column chromatography with silica gel, eluting with toluene/ethylacetate (1/1 v/v) to prepare 1.07 g (Yield: 80%) of the objectivecompound (Ia-18) as an oil.

mp. 158.5°-159.5° C. (dec.).

Anal Calcd. (%) for C₂₆ H₃₉ N₃ O₂.C₂ H₂ O₄.1/2H₂ O: C, 64.38; H, 8.11;N, 8.05. Found: C, 64.10; H, 8.07; N, 8.01.

IR (Nujol): 3420, 2720, 2590, 2500, 1715, 1692, 1675(sh), 1610(br),1515, 1460.

NMR (CD₃ OD) (200 MHz) δ:0.894 (t, J=7 Hz, 3H); 1.312 (s, 9H); 1.618 (q,J=7 Hz, 2H); 2.117 (quint, J=7 Hz, 4H); 2.458 (t, J=8 Hz, 2H); 2.872(brs, 2H); 3.28-3.37 (m, 4H); 3.49-3.56 (m, 4H); 3.695 (t, J=7 Hz, 2H);3.932 (brs, 2H); 6.089 (quint, J=2 Hz, 1H); 7.402 (s, 4H).

EXAMPLE 191-[3-{4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propyl]pyrrolidine(Ia-19) ##STR23##

(1) A mixture of 10.061 g of the compound (II-6) and 5.41 ml of3-chloro-1-propanol is stirred at 140° C. for 6 hours in the presence of12.03 ml of Et₃ N. The reaction mixture is recrystallized from methylenechloride-ether-n-hexane to prepare 9.357 g (Yield: 74.0%) of thecompound (IV-3). mp. 122.5°-123.5° C.

Anal Calcd. (%) for C₁₈ H₂₉ NO₂.1/10H₂ O C,73.72; H,9.93; N,4.82. Found:C,73.73; H,10.04; N,4.78.

IR (CHCl₃) cm⁻¹ : 3600, 3225, 1509, 1472, 1437, 1424, 1399, 1372 (sh),1366.

NMR (CDCl₃) δ:1.31 (s, 9H); 1.62-1.85 (m, 4H); 2.119 (td, J₁ =13 Hz, J₂=4 Hz, 2H); 2.507 (td, J₁ =12 Hz, J₂ =2 Hz, 2H); 2.707 (t, J=6 Hz, 2H);2.973 (d, J=11 Hz, 2H); 3.829 (t, J=6 Hz, 2H); 7.367, 7.417 (ABq, J=8Hz, 4H).

(2) A mixture of 10.568 g of the compound (IV-3) and 26.4 ml of thionylchloride is stirred at room temperature overnight. Excess reagent isdistilled off under reduced pressure, and the residue is poured intoaq.Na₂ CO₃. The solution is extracted with methylene chloride, and theorganic layer is dried over MgSO₄ and concentrated. The residue issubjected to column chromatography with silica gel, eluting withtoluene/acetone (8/1-6/1 v/v) and recrystallized from n-hexane toprepare 2.167 g (Yield: 20.5%) of the compound (V-1) as colorlesscrystals.

Anal Calcd. (%) for C₁₈ H₂₆ NCl: C, 73.86; H, 9.08; N, 4.96; Cl, 12.35.Found: C, 74.07; H, 8.98; N, 4.80; Cl, 12.15.

IR (CHCl₃): 1640, 1610, 1510, 1470, 1390, 1380.

NMR (CDCl₃): 1.315 (s, 9H); 2.041 (quint, J=7 Hz, 2H); 2.50-2.66 (m,4H); 2.714 (t, J=5 Hz, 2H); 3.169 (q, J=3 Hz, 2H); 3.638 (t, J=7 Hz,2H); 6.032 (quint, J=3H, 1H); 7.334 (s, 4H).

(3) A mixture of 621 mg of the compound (V-1) and 1.78 ml of pyrrolidineis stirred at room temperature for 72 hours. The excess reagent isdistilled off, and the residue is subjected to column chromatographywith silica gel, eluting with methylene chloride/methanol/ammonia(128/16/1 v/v) to prepare 675 mg of the compound (Ia-19) as an oil,which is crystallized as maleate and recrystallized from methanol togive 800 mg (yield: 67.3%) of colorless plates. mp. 190.0°-191.0° C.(dec.).

Anal Calcd. (%) for C₂₂ H₃₄ N₂ O₂.C₄ H₄ O₄ : C, 64.74; H, 7.58; N, 5.11.Found: C, 64.50; H, 7.58; N, 5.01.

IR (Nujol): 2355, 1711, 1620, 1577, 1543, 1479(sh), 1461, 1378.

NMR (CD₃ OD) δ:1.314 (s, 9H); 2.122 (quint, J=3 Hz, 2H); 2.20-2.37 (m,2H); 2.907 (brs, 2H); 3.30-3.43 (m, 6H); 3.567 (t, J=6 Hz, 2H); 3.949(brs, 2H); 6.129 (brs, 1H); 6.269 (s, 2H); 7.416 (s, 4H).

EXAMPLE 201-[3-{4-(4-trifluoromethyl)-1,2,5,6-tetrahydropyridin-1-yl}-propyl]pyrrolidine(Ia-20) ##STR24##

(1) A mixture of 5.00 g of the compound (II-2) and 2.22 ml of3-chloro-1-propanol is stirred in the presence of 4.27 ml of Et₃ N at140° C. for 8 hours. The mixture is subjected to column chromatographywith silica gel, eluting with methylenechloride/methanol/ammonium=64/8/1-32/6/1 v/v. The obtained purifiedsubstance is recrystallized from ether-n-hexane to prepare 5.155 g(Yield: 75.7%) of the compound (IV-4). mp. 116.0°-116.5° C.

Anal Calcd. (%) for C₁₅ H₂₀ NO₂ F₃ : C, 59.31; H, 6.59; N, 4.69; F,18.70. Found: C, 59.40; H, 6.65; N, 4.62; F, 18.79.

IR (Nujol): 3335, 3075, 2773, 1617, 1462, 1436, 1407, 1378.

NMR (CDCl₃) δ:1.73-1.83 (m, 4H); 2.119 (td, J₁ =13 Hz, J₂ =4 Hz, 2H);2.494 (td, J₁ =12 Hz, J₂ =3 Hz, 2H); 2.716 (t, J=6 Hz, 2H); 3.009 (d-d,J₁ =12 Hz, J₂ =2 Hz, 2H); 3.836 (t, J=6 Hz, 2H); 7.612 (s, 4H).

(2) The compound (IV-4) 4.892 g is treated in the same manner as Example19(2) to prepare 3.357 g of the compound (V-2) as an oil.

IR (CHCl₃): 1608, 1453, 1439, 1399, 1368(sh), 1319.

NMR (CDCl₃): 2.036 (quint, J=7 Hz, 3H); 2.54-2.62 (m, 2H); 2.636 (t, J=7Hz, 2H); 2.733 (t, J=6 Hz, 2H); 3.192 (q, J=3 Hz, 2H); 3.635 (t, J=7 Hz,2H); 6.152 (quint, J=2 Hz, 1H); 7.466, 7.562 (ABq, J=8 Hz, 4H).

(3) A mixture of 1.05 g of the compound (V-2) and 1.44 ml of pyrrolidineis stirred at room temperature for 32.5 hours, and the reaction mixtureis treated in the same manner as Example 19 (3) to prepare 1.15 g(Yield: 98.2%) of the objective compound (Ia-20) as crystals. Themalenate is recrystallized from methanol to prepare 1.04 g (Yield:98.2%) of colorless needles. mp. 175.0-178.0 (dec.).

Anal. Calcd. (%) for C₁₉ H₂₅ N₂ F₃ O₂.C₄ H₄ O₄ C, 57.92; H, 5.74; N,4.97; F, 10.05. Found: C, 56.84; H, 5.83; N, 4.91; F, 9.99.

IR (Nujol): 2590, 2360, 2160, 1711, 1620, 1560, 1535(sh), 1483, 1458,1378, 1359.

NMR (CD₃ OD): 2.119 (quint, J=3 Hz, 4H); 2.20-2.37 (m, 2H); 2.92 7 (brs,2H); 3.28-3.50 (m, 8H); 3.566 (t, J=6 Hz, 2H); 3.971 (q, J=2 Hz, 2H);6.266 (s, 4H); 6.295 (brs, 1H); 7.681 (s, 4H).

EXAMPLE 211-[3-{4-(4-methylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propyl]pyrrolidine(Ia-21) ##STR25##

(1) A mixture of 10.20 g of the compound (II-8) and 5.51 ml of3-chloro-1-propanol is stirred in the presence of 11 ml of Et₃ N at 140°C. for 5.5 hours. The reaction mixture is recrystallized from methylenechloride-ether to prepare 8.51 g (Yield: 64.0%) of the compound (IV-5).mp. 110.5°-111.5° C.

Anal Calcd. (%) for C₁₅ H₂₃ NO₂ : C, 72.01; H, 9.25; N, 5.58. Found: C,72.25; H, 9.30; N, 5.62.

IR (CHCl₃): 3597, 3220, 1513, 1470, 1452, 1437, 1423, 1397.

NMR (CDCl₃) δ:1.67-1.81 (m, 4H); 2.087 (td, J₁ =13 Hz, J₂ =4 Hz, 2H);2.337 (s, 3H); 2.479 (td, J₁ =15 Hz, J₂ =3 Hz, 2H); 2.693 (t, J=6 Hz,2H); 2.952 (d, J=11 Hz, 2H); 3.828 (t, J=5 Hz, 2H); 7.168, 7.372 (ABq,J=8 Hz, 4H).

(2) A solution of 12.82 g of the compound (IV-5) in 38 ml oftrifluoroacetic acid is refluxed for 3.1 hours. The reaction mixture isconcentrated, and the residue is poured into aq.NaHCO₃. The mixture isextracted with ethyl acetate, and the organic layer is dried over MgSO₄and concentrated under reduced pressure. The oily substance is subjectedto column chromatography with silica gel, eluting with methylenechloride/methanol/NH₄ OH (128/16/1 v/v). A mixture of 870 mg of theproduct and 8.01 ml of thionyl chloride is stirred at room temperaturefor 2 hours. The excess reagent is distilled away under reducedpressure. The residue is washed with ether and dried under reducedpressure to give 1.067 g (Yield: 99.2%) of the objective compound (V-3)as a light yellowish powder.

IR (CHCl₃): 1600, 1510, 1460, 1410.

NMR (CDCl₃): 2.046 (quint, J=7 Hz, 2H); 2.334 (s, 3H); 2.54, 2.64 (m,2H); 2.629 (t, J=7 Hz, 2H); 2.723 (t, J=5 Hz, 2H); 3.173 (q, J=2 Hz,2H); 3.630 (t, J=7 Hz, 2H); 6.023 (quint, J=2 Hz, 1H); 7.123, 7.287(ABq, J=8 Hz, 4H).

(3) A mixture of 466 mg of the compound (V-3) and 0.78 ml of pyrrolidineis stirred at 50° C. for 3 hours and treated in the same manner asExample 19(3) to give the maleate of the objective compound (Ia-21). Itis recrystallized from methanol-iPrOH to prepare 225 mg (Yield: 42.5%)of the compound (Ia-21) as needles. mp. 180.0°-181.0° C. (dec.)

Anal Calcd. (%) for C₁₉ H₂₈ N₂.2C₄ H₄ O₄ : C, 62.84; H, 6.99; N, 5.48.Found: C, 62.78; H, 7.02; N, 5.42.

EXAMPLE 22-29

The compound (V-1), (V-2) and (V-3), each of which were obtained in Step1 of Example 19-21, are reacted with amine (VII) in the same manner asStep 3 in Example 19-21 to prepare the compound (Ia). The reactionconditions and physical constants are shown in table 5 and 6.

                                      TABLE 5                                     __________________________________________________________________________     ##STR26##                                                                     ##STR27##                                                                    Ex.                                                                              starting          reaction                                                                            purification product                               No.                                                                              material                                                                           RH           condition                                                                           condition    mg (%)                                __________________________________________________________________________    22 (V-1)                                                                              HN(i-Bu).sub.2                                                                             33 hours                                                                            CH.sub.2 Cl.sub.2 /MeOH =                                                                  Ia-22*.sup.1                             0.628 g                                                                            3.76 ml      reflux                                                                              49/1-19/1    685 mg                                                                        (51.1%)                               23 (V-2)                                                                              HN(i-Bu).sub.2                                                                             32 hours                                                                            CH.sub.2 Cl.sub.2 /MeOH =                                                                  Ia-23*.sup.1                             0.602 g                                                                            1.50 g       reflux                                                                              49/1-19/1    338 mg                                                                        (27.1%)                               24 (V-3)                                                                              HN(i-Bu).sub.2                                                                             20 hours                                                                            CH.sub.2 Cl.sub.2 /MeOH =                                                                  Ia-24*.sup.1                             0.517 g                                                                            1.36 g       reflux                                                                              49/1         457 mg                                                                        (38.4%)                               25 (V-3) 0.924 g                                                                       ##STR28##   150° C. 8.15 hours                                                           toluene/acetone = 19/1-9/1                                                                 Ia-25*.sup.1 930 mg (54.4%)           26 (V-3) 0.624 g                                                                       ##STR29##   150° C. 4.1 hours                                                            CH.sub.2 Cl.sub.2 /MeOH = 19/1                                                             Ia-26*.sup.1 963 mg 66.6%)            27 (V-2) 1.02 g                                                                        ##STR30##   100° C. 25 hours (in DMF)                                                    toluene/acetone = 3/11/1                                                                   Ia-27*.sup.1 266 mg (15.3%)           28 (V-2)                                                                              H.sub.2 N-i-Bu                                                                             15.6 hours                                                                          CH.sub.2 Cl.sub.2 :MeOH:NH.sub.4 OH                                                        Ia-28                                    0.645 g                                                                            1.1 ml       reflux                                                                              64/8/1       461 mg                                                                        (63.8%)                               29 (V-1) 0.828 g                                                                       ##STR31##   150° C. 3 hours                                                              CH.sub.2 Cl.sub.2 /MeOH = 29/1-19/1                                                        Ia-29*.sup.1 773                      __________________________________________________________________________                                            mg (70.2%)                             *.sup.1 separated as maleate                                                  *.sup.2 prepared by the reaction with 492 mg of isoindoline and 162 mg of     60% NaH in 5 ml of DMF at 100° C. for 1 hour.                     

                                      TABLE 6                                     __________________________________________________________________________    Compd.                                                                             mp. (°C.)                                                                       Anal Cald. (%)                                                  No.  Rec. sol.*.sup.1                                                                       Found (%)     IR (cm.sup.-1)                                                                        NMR (δ) (200MHz)                    __________________________________________________________________________    Ia-22                                                                              (maleate)                                                                              C.sub.26 H.sub.44 N.sub.2 O.sub.2.C.sub.4 H.sub.4 O.sub.4                                   (Nujol) (CD.sub.3 OD)                                  176.5˜178.0                                                                      C, 63.46 (63.68)                                                                            2620, 2510, 1690                                                                      1.083(d, J=7Hz, 12H); 1.314(s, 9H);                                           2.158(7tet, J=7Hz,                             (MeOH--Et.sub.2 O)                                                                     H, 8.02 (8.18)                                                                              1657, 1618, 1579                                                                      2H); 2.20-2.37(m, 2H); 2.913(brs,                                             2H); 3.042(d, J=7Hz,                           needleshaped                                                                           N, 6.83 (6.75)                                                                              1533, 1488, 1460                                                                      4H); 3.25-3.37(m, 4H); 3.588(t,                                               J=6Hz, 2H); 3.974(s, 2H);                      crystals F, 7.98 (8.54)                                                                              1409, 1378                                                                            6.131(s, 1H); 6.272(s, 4H); 7.419(s,                                          4H)                                       Ia-23                                                                              (maleate)                                                                              C.sub.23 H.sub.35 N.sub.2 F.sub.3 O.sub.2.C.sub.4 H.sub.4                     O.sub.4       (Nujol) (CD.sub.3 OD)                                  135.0˜136.5                                                                      C, 59.12 (59.23)                                                                            2420, 1707, 1616                                                                      1.071(d, J=7Hz, 12H); 2.05-2.35(m,                                            4H); 2.90-3.30(m,                              (MeOH--Et.sub.2 O)                                                                     H, 6.76 (6.89)                                                                              1572, 1485, 1456                                                                      4H); 3.20-3.30(m, 4H); 3.559(brs,                                             2H); 3.972(brs, 2H);                           needleshaped                                                                           N, 4.35 (4.46)                                                                              1377    J=7Hz, 2H) 2.54-2.61(m, 2H); 2.747(t,                                         J=5Hz, 2H);                                    crystals F, 9.05 (9.07)        6.260(s, 5H); 7.674(s, 4H)                Ia-24                                                                              (maleate)                                                                              C.sub.23 H.sub.38 N.sub.2.C.sub.4 H.sub.4 O.sub.4                                           (Nujol) (CDCl.sub.3)                                   140.5˜142.5                                                                      C, 64.67 (64.79)                                                                            2710, 2500, 1706                                                                      0.872(d, J=7Hz, 12H); 1.685(quint,                                            J=7Hz, 4H); 2.059(d,                           (MeOH--Et.sub.2 O)                                                                     H, 7.99 (8.07)                                                                              1572, 1480, 1455                                                                      J=7Hz, 4H); 2.329(s, 3H);                                                     2.33-2.60(m, 6H); 2.712(t,                     needleshaped                                                                           N, 4.69 (4.87)                                                                              1375    J=5Hz, 2H); 3.161(q, J=3Hz, 2H);                                              6.021(quint, J=2Hz,                            crystals                       1H); 7.116, 7.283(ABq, J=9Hz, 4H)         Ia-25                                                                              (maleate)                                                                              C.sub.24 H.sub.30 N.sub.2 O.sub.2.C.sub.4 H.sub.4 O.sub.4                                   (Nujol) (CD.sub.3 OD)                                  148.0˜150.0                                                                      C, 72.65 (72.70)                                                                            2720, 2575(sh),                                                                       1.80-2.01(m, 4H); 2.331(s, 3H);                                               2.48-2.63(m, 4H); 2.712(t,                     (iPrOH--Et.sub.2 O)                                                                    H, 7.36 (7.41)                                                                              2490(sh), 2330,                                                                       J=7Hz, 2H); 2.747(t, J=7Hz, 2H);                                              3.162(q, J=3Hz, 2H);                                    N, 6.11 (6.06)                                                                              1708, 1652, 1600                                                                      3.283(t, J=6Hz, 2H); 3.329(t, J=7Hz,                                          2H); 6.026(quint,                                                     1571, 1502, 1459                                                                      J=2Hz, 1H); 6.50-6.64(m, 2H);                                                 6.91-7.32(m, 6H)                          Ia-26                                                                              (maleate)                                                                              C.sub.24 H.sub.30 N.sub.2 O.sub.2.C.sub.4 H.sub.4 O.sub.                                    (Nujol) (CDCl.sub.3)                                   191.0˜192.0                                                                      C, 66.48 (66.42)                                                                            3030, 2720, 2278                                                                      1.322(s, 9H); 1.76-1.94(m, 8H);                                               2.262(t-d, J.sub.1 =14Hz,                      (MeOH--H.sub.2 O)                                                                      H, 6.61 (6.62)                                                                              1711, 1623, 1572                                                                      J.sub.2 =4Hz, 2H); 2.50-2.65(m, 4H);                                          2.951(d, J=11Hz, 2H);                          needleshaped                                                                           N, 4.92 (4.84)                                                                              1532, 1513(sh),                                                                       3.30-3.39(m, 4H); 5.738(brs, 1H);                                             7.378, 7.418(ABq,                              crystals               1485, 1463, 1435                                                                      J=8Hz, 4H)                                Ia-27                                                                              (maleate)                                                                              C.sub.23 H.sub.23 F.sub.3 N.sub.2 O.C.sub.4 H.sub.4                                         (CHCl.sub.3)                                                                          (CD.sub.3 OD)                                  152.5˜154.0                                                                      C, 62.64 (62.79)                                                                            2700-1750 (br):                                                                       2.236(quint, J=7Hz, 2H); 2.934(brs,                                           2H); 3.334(t, J=7Hz,                           (MeOH--Et.sub.2 O)                                                                     H, 5.29 (5.27)                                                                              1695, 1663, 1619                                                                      2H); 2.369(t, J=5Hz, 2H); 3.808(t,                                            J=7Hz, 2H); 4.010(s,                           needleshaped                                                                           N, 5.48 (5.42)                                                                              1532, 1463, 1412                                                                      2H); 4.606(s, 2H); 6.230(brs, 2H);                                            6.298(brs, 1H);                                crystals F, 11.00 (11.03)                                                                            1378, 1358                                                                            7.51-7.81(m, 9H)                          Ia-28                                                                              (maleate)                                                                              C.sub.19 H.sub.27 N.sub.2 F.sub.3.C.sub.4 H.sub.4 O.sub.4                                   (Nujol) (CDCl.sub.3)                                   182.5˜184.0                                                                      --            3483, 2723, 2679                                                                      0.952(d, J=7Hz, 6H); 2.093(quint,                                             J=7Hz, 3H); 2.636(brs,                         (MeOH--Et.sub.2 O)     2587, 2415, 1703                                                                      2H); 2.727(d, J=7Hz, 2H); 2.771(t,                                            J=6Hz, 2H); 2.898(t,                           needleshaped           1618, 1579, 1478                                                                      J=6Hz, 2H); 3.149(t, J=6Hz, 2H);                                              3.29-3.33(m, 2H);                              crystals               1460, 1412, 1382                                                                      6.184(quint, J=2Hz, 1H); 7.474,                                               7.587(ABq, J=8Hz, 4H)                     Ia-29                                                                              (maleate)                                                                              C.sub.27 H.sub.36 N.sub.2.2C.sub.4 H.sub.4 O.sub.4.1/10H.sub                  .2 O          (Nujol) (CD.sub.3 OD)                                  183.5˜185.0                                                                      C, 67.29 (67.59)                                                                            2340, 1708, 1619                                                                      1.330(s, 9H); 2.424(brs, 2H);                                                 2.867(brs, 2H); 3.204(brs,                     (CHCl.sub.3 --MeOH)                                                                    H, 7.08 (7.16)                                                                              1568, 1528(sh),                                                                       2H); 3.370(brs, 4H); 3.544(brs, 4H);                                          3.948(s, 2H); 4.403(s,                         needleshaped                                                                           N, 4.56 (4.50)                                                                              1485, 1461                                                                            2H); 6.060(s, 1H); 6.252(s, 4H);                                              7.15-7.44(m, 8H)                               crystals                                                                 __________________________________________________________________________     *.sup.1 a solvent for recrystallization                                  

EXAMPLE 301-[(3-methylamino)propyl]-4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridine(Ia-30) ##STR32##

(1) A solution of 3.60 g of the compound (II-6) and 2.80 g of1-ethoxycarbonylamino-3-chloropropane in 30 ml of DMF is reacted in thepresence of 4.26 g of K₂ CO₃ and 3.46 g of NaI at 105°-110° C. for 6hours. The reaction mixture is poured into ice water and extracted withethyl acetate. The ethyl acetate layer is washed with water, dried overMgSO₄ and evaporated under reduced pressure. The residue is subjected tocolumn chromatography with silica gel, eluting with methylenechlorde/methanol (10/1-5/1 v/v) to give 4.60 g (Yield: 82.0%) of thecompound (IV-6) as crystals. Recrystallization from methylenechloride-ether gives colorless needles. mp. 111.5°-113.0° C.

Anal Calcd. (%) for C₂₁ H₃₄ N₂ O₃.1/5H₂ O: C, 68.92; H, 9.37; N, 7.78Found: C, 68.89; H, 9.47; N, 7.65

IR (Nujol): 3320, 1715, 1700, 1535

NMR (CDCl₃) δ:1.242 (t, J=7 Hz, 3H); 1.320 (s, 9H); 1.66-1.84 (m, 4H);2.210 (td, J₁ =13 Hz, J₂ =4 Hz, 2H) 2.45-2.60 (m, 4H); 2.877 (d, J=12Hz, 2H); 3.286 (q, J=6 Hz, 2H); 4.103 (q, J=7 Hz, 2H); 5.929 (brs, 1H);7.376,7.443 (ABq, J=8 Hz, 4H)

(2) A solution of 4.30 g of the compound (IV-6) obtained above in 35 mlof trifluoroacetic acid is refluxed for 5 hours and treated in the samemanner as Example 7(2) to prepare 4.05 g (Yield: 99.0%) of the compound(V-4) as an oil.

(3) To a suspension of 146 mg of lithium aluminium hydride in 15 ml ofdry ether is added dropwise a solution of 530 mg of the compound (V-4)in 15 ml of THF under stirring. After reflux for 8 hours, the excessreagents are decomposed by careful addition of aq. NaOH and filteredoff. The resulting organic layer is dried and evaporated under reducedpressure to prepare 420 mg (Yield: 95.2%) of the compound (Ia-30) as anoil.

IR (CHCl₃):3290, 1602, 1510, 1470, 1445.

NMR (CDCl₃):1.321 (s, 9H); 1.780 (quint, J=7 Hz, 2H); 2.444 (s, 3H);2.48-2.62 (m, 2H); 2.532 (t, J=7 Hz, 2H); 2.672 (t, J=7 Hz, 2H); 3.152(q, J=3 Hz, 2H); 6.039 (quint, J=2 Hz, 1H); 7.333 (s, 4H)

EXAMPLE 311-[N-methyl-N-[3-{4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propylcarbamoyl]]-2-oxopyrrolidine(Ia-31) ##STR33##

A mixture of 400 mg of the compound (Ia-30) obtained in Example 30 and280 mg of 1-phenoxycarbonyl-2-oxopyrrolidine is heated at 115° C. for 2hours. The reaction mixture is subjected to column chromatography withsilica gel, eluting with toluene/ethyl acetate (1/1)-methylenechloride/methanol (20/1) to prepare 370 mg (Yield: 68.5%) of thecompound (Ia-31) as an oil. The tosylate is recrystallized from ethylacetate/methanol to prepare needles.

mp. 128.0°-134.0° C.

Anal Calcd. (%) for C₂₄ H₃₅ N₃ O₂.C₇ H₈ O₃ S.H₂ O: C, 63.51; H, 7.56; N,7.16; S, 5.37 Found:C, 63.35; H, 7.72; N, 7.15; S, 5.45

IR (Nujol) cm⁻ :3570, 3500, 2740, 2630, 1720, 1690, 1675(sh), 1663,1475, 1120, 1033.

NMR (CDCl₃) δ:1.314 (s, 9H); 1.895 (quint, J=7 Hz, 2H); 2.071 (quint,J=7 Hz, 2H); 2.454 (t, J=8 Hz, 2H); 2.50-2.60 (m, 4H); 2.720 (t, J=5 Hz,2H); 2.995 (s, 3H); 3.174 (q, J=3 Hz, 2H); 3.461 (t, J=7 Hz, 2H); 3.735(t, J=7 Hz, 2H); 6.024 (quint, J=2 Hz, 1H); 7.244, 7.348 (ABq, J=8 Hz,4H)

EXAMPLE 321-[(3-methylamino)propyl]-4-(4-phenylphenyl-1,2,5,6-tetrahydropyridine(Ia-32) ##STR34##

(1) A solution of 3.20 g of the compound (II-5) and 2.30 g of1-ethoxycarbonylamino-3-chloropropane in 30 ml of DMF is reacted in thepresence of 3.48 g of K₂ CO₃ and 2.83 g of NaI at 105° C. for 41 hours.The reaction mixture is poured into ice water and extracted with ethylacetate. The ethyl acetate layer is washed with water, dried over MgSO₄and evaporated under reduced pressure. The residue is subjected tocolumn chromatography with silica gel, eluting with methylenechloride/methanol (10/1-5/1v/v). The resulting purified substance isrecrystallized from methylene chloride to prepare 2.46 g (Yield: 51.0%)of the compound (IV-7).

mp. 138.0°-139.0° C.

Anal Calcd. (%) for C₂₃ H₃₀ N₂ O₃ : C, 72.22; H, 7.84; N, 7.30 Found: C,72.22; H, 7.91; N, 7.32

IR (CHCl₃) cm⁻¹ :3600, 3450, 1705, 1602, 1512, 1490.

NMR (CDCl₃) δ: 1.240 (t, J=7 Hz, 3H); 1.60-1.80 (m, 4H); 1.830 (s, 1H);2.195 (t-d, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.480 (d-d, J₁ =14 Hz, J₂ =2 Hz,2H); 2.524 (t, J=7 Hz, 2H); 2.850 (d, J=14 Hz, 2H); 3.280(q, J=6 Hz,2H); 4.101 (q, J=7 Hz, 2H); 6.962 (brs, 1H); 7.25-7.70 (m, 9H) 9H).

(2) A solution of 2.29 g of the compound (IV-7) in 25 ml oftrifluoroacetic acid is refluxed for 9.5 hours and treated in the samemanner as Example 7 (2) to prepare 2.08 g (Yield: 95.3%) of the compound(V-5). mp. 135.0°-138.0° C.

(3) To a solution of 1.80 g of the compound (V-5) in 26 ml of THF isadded dropwise 375 mg of lithium alminium hydride. After reflux for 8hours, the reaction mixture is treated in the same manner as Example 29(3) to prepare (Ia-32) as an oil.

EXAMPLE 331-[3-{4-(4-phenylphenl)-1,2,5,6-tetrahydropyridin-1-yl}propylmethylcarbamoyl]-2-oxopyrrolidine(Ia-33) ##STR35##

To the compound (Ia-32) obtained Example 32 is added dropwise 810 mg of1-phenoxycarbonyl-2-oxopyrrolidine, and the mixture is heated at115°-120° C. for 5 hours. The reaction mixture is subjected to columnchromatography with silica gel, eluting with methylene chloride/methanol(20/1 v/v) to prepare 650 mg (Yield: 31.5%) of the compound (Ia-33). Theoxalate is recrystallized from i-PrOH to give needles. mp. 186.0°-187.0°C. (dec.).

Anal Calcd. (%) for C₂₆ H₃₁ N₃ O₂.C₂ H₂ O₄.1/2H₂ O: C, 64.71; H, 6.52;N,7.97. Found: C, 65.10; H, 6.63; N,8.13.

IR (Nujol): 3500(br), 2720, 2600, 1720, 1665, 1485, 1455, 1405, 1405,1375.

NMR (CDCl₃) δ:1.900 (quint, J=7 Hz, 2H); 2.107 (quint, J=7 Hz, 2H);2.455 (t, J=8 Hz, 2H); 2.55-2.64 (m, 4H); 2.741 (t, J=5 Hz, 2H); 3.002(s, 3H); 3.198 (q, J=3 Hz, 2H); 3.469 (t, J=7 Hz, 2H); 3.737 (t, J=7 Hz,2H); 6.124 (quint, J=2 Hz, 1H) 7.3-7.6 (m, 9H).

EXAMPLE 341-[3-(N-methyl-N-isobutyl)aminopropyl]-4-(4-trifluoromethylphenyl)-1,2,5,6-tetrahydropyridine(Ia-34) ##STR36##

A mixture of 342 mg of the compound (Ia-23), 1 ml of formaldehyde, and 1ml of formic acid is stirred at 70° C. for 3 hours and 40 minutes. Thereaction mixture is concentrated, and the residue is poured intoaq.NaHCO₃. The solution is extracted with methylene chloride-methanol,and the organic layer is dried over MgSO₄ and evaporated under reducedpressure. The resulting oily substance is subjected to columnchromatography with silica gel, eluting with methylene chloride/methanol(19/1-5/1 v/v) to prepare 252 mg of the objective compound (Ia-34). Themaleate is recrystallized from ethnol-ether to prepare 325 mg (Yield:55.2%) of colorless needles. mp. 182.0°-183.5° C.

Anal Calcd. (%) for C₂₀ H₂₉ N₂ F₃.2C₄ H₄ O₄ : C, 57.16; H, 6.32; N,4.82; F, 9.46. Found: C, 57.33; H, 6.36; N, 4.78; F, 9.72.

IR (Nujol): 2360, 1708, 1621, 1570, 1533, 1481, 1460, 1447(sh), 1377,1359.

NMR (CDCl₃): 0.938 (d, J=7 Hz, 6H); 1.826 (quint, J=7 Hz, 3H); 2.212 (d,J=7 Hz, 2H); 2.309 (s, 3H); 2.513 (t, J=7 Hz, 2H); 2.548 (t, J=7 Hz,2H); 2.58, 2.63 (m, 2H); 2.747 (t, J=5 Hz, 2H); 3.208 (q, J=3 Hz, 2H);6.161 (quint, J=2 Hz, 1H); 7.474, 7.567 (ABq, J=8 Hz, 4H).

EXAMPLE 354-[3-{4-(4-tert-butylphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propyl]morpholine(Ia-35) ##STR37##

(1) A mixture of 1.09 g of the compound (IV-2) obtained in Example 18and 1.4 g of morpholine is refluxed for 4 hours. After removal of theexcess reagent under reduced pressure, the residue is poured into aq.Na₂SO₄ and evaporated. The residue is purified by column chromatographywith silic gel, eluting with mthylene chloride/methanol (20/1 v/v). Thehydrochloride of the compound (III-19) is crystallized from methylenechloride-ether to prepare 850 mg (Yield: 66.3%) of needles. mp. 242° C.(dec.)

NMR (CDCl₃.CD₃ OD=10/1): 1.307 (s, 9H); 2.10-2.22 (m, 2H); 2.48-2.55 (m,4H); 2.760 (td, J₁ =15 Hz, J₂ =4 Hz, 2H); 3.06-3.15 (m, 4H); 3.25-3.50(m, 4H); 3.731 (t, J=5 Hz, 4H); 7.387, 7.454 (ABq, J=9 Hz, 4H).

(2) A solution of 880 mg of the compound (III-19) in 10 ml oftrifluoroacetic acid is refluxed for 8 hours and evaporated underreduced pressure. The residue is poured into aq. sodiumhydrogencarbonate, and extracted with methylene chloride. The organiclayer is washed with saline, dried over Na₂ SO₄ and evaporated. Theresidue is purified by column chromatography followed by crystallizationas the maleate. Recrystallization from methanol gives 760 mg (Yield:97.5%) of reddish needles.

mp. 213.0°-214.5° C. (dec.).

Anal Calcd. (%) for C₂₂ H₃₄ N₂ O.2C₄ H₄ O₄ : C, 62.63; H, 7.35; N, 4.93.Found: C, 62.70; H, 7.37; N, 4.87.

IR (Nujol): 2300 (br); 1717, 1622, 1675, 1535, 1500, 1465, 1458,1450(sh).

NMR (CDCl₃): 1.314 (s, 9H); 1.783 (quint, J=7 Hz, 2H); 2.36, 2.63 (m,8H); 2.709 (t, J=5 Hz, 2H); 3.164 (q, J=3 Hz, 2H); 3.725 (t, J=5 Hz,2H); 6.031 (quint, J=1 Hz, 1H); 7.330 (s, 4H).

EXAMPLE 36-71

The reaction is performed in the same manner as Example 1 to prepare thecompound (Ia). The reaction conditions are shown in Table 7 and 8.Further the physical constants of the compound (Ia) obtained in Example36-71 are shown in Table 9.

    TABLE 7       starting     reaction  g (%)   Exam. material  DMF K.sub.2 CO.sub.3     NaI condition (1) purification Compd. No. X = R(CH.sub.2).sub.n Y (VI)     (ml) (g) (g) (°C., hr.) condition No. m.p. (°C.) IR     (cm.sup.-1)      ##STR38##      (Step 1)            36 Me(p)2.50 g(II-8)      ##STR39##      35 4.53 2.95 105-110 7 hr. CH.sub.2 Cl.sub.2 /MeOH =      10/1 3.46(76.4)(III-20) 116.0˜117.0 (CHCl.sub.3)3600, 3320,     1713,1688(sh), 1680,1545, 1490      37 Me(p)2.34 g(II-8)     ##STR40##      25 4.21 2.74 105 6 hr. toluene/ethyl acetate =      20/1-10/1 3.07(70.0)(III-21) 143.5˜144.5 (CHCl.sub.3)3600, 3320,     1715,1618, 1550-1520  38 Me(m) (VI-1) 2.35 g 30 3.18 2.59 105-110 8 hr.     CH.sub.2 Cl.sub.2 /MeOH = 10/1 1.70 -- (CHCl.sub.3)  1.85 g       (49.0)      3600, 3320, 1715,  (II-9)       (III-22)  1680, 1608, 1545,     1490, 1470 39 Me(o) (VI-1) 2.68 g 35 4.53 2.95 105-110 7 hr. CH.sub.2     Cl.sub.2 /MeOH = 10/1 3.18 -- (CHCl.sub.3)  2.50 g       (67.5)  3600,     3320, 1712,  (II-10)       (III-23)  1680, 1600, 1545,           1489,     1470, 1460 40 3,4-di-Me (VI-1) 2.09 g 35 2.82 2.29 105 7 hr. CH.sub.2     Cl.sub.2 /MeOH = 10/1 2.56 -- --  2.10 g       (67.2)  (II-11)     (III-24) 41 3,5-di-Me (VI-1) 2.81 g 35 3.79 3.08 105° C. 6 hr.     CH.sub.2 Cl.sub.2 /MeOH = 10/1 3.81 -- (CHCl.sub.3)  2.82 g       (74.4)      3595, 3310, 1715,  (II-12)       (III-25)  1680, 1590, 1565,     1545, 1489, 1470           1460. 42 Cl(m) (VI-1) 2.49 g 30 4.18 2.72     105-110° C. 7 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1-10/1 3.78     90.5˜91.5 (CHCl.sub.3)  2.70 g       (81.8)  3600, 3220, 1713,     (II-13)       (III-26)  1658, 1595, 1545,           1490, 1470, 1460 43     Cl(m) (VI-7) 2.31 g 30 4.18 2.72 105-110° C. 7 hr. CH.sub.2     Cl.sub.2 /MeOH = 10/1 3.30 94.0-98.0 (Nujol)  2.70 g       (74.3)  3280,     2720-2520,  (II-13)       (III-27)  1713, 1685, 1600,           (sh),     1588, 1560 44 Cl(o) (VI-1) 2.42 g 30 4.08 2.65 105-110 6 hr. ethyl     acetate/toluene = 1/1 2.10 -- (CHCl.sub.3)  2.50 g      CH.sub.2     Cl.sub.2 /MeOH = 15/1 (46.7)  3580, 3320, 1715,  (II-14)       (III-28)     1680, 1547 45 Cl(o) (VI-7) 1.28 g 20 2.32 1.51 105-110 6 hr. CH.sub.2     Cl.sub.2 /MeOH = 15/1 0.840 -- (CHCl.sub.3)  1.45 g       (34.1)  3580,     3220, 1715,  (II-14)       (III-29)  1680, 1545(sh), 1540(sh),     1525 46 3,5-diCl (VI-1) 3.0 g 35 4.04 3.28 105° C. 7.0 hr.     CH.sub.2 Cl.sub.2 /MeOH = 10/1 5.25 138.0-140.0 (CHCl.sub.3)  3.86 g       (86.8)  3595, 3310, 1715,  (II-15)       (III-30)  1680, 1590, 1565,             1545 47 Br(p) (VI-1) 1.96 g 25 2.64 2.15 105° C. 8 hr.     CH.sub.2 Cl.sub.2 /MeOH = 10/1 3.16 -- (CHCl.sub.3)  2.57 g       (77.9)      3590, 3310, 1713,  (II-16)       (III-31)  1680, 1545, 1489,     1460 48 F(p) (VI-1) 4.20 g 50 7.08 4.61 105-110° C. 6.0 hr.     CH.sub.2 Cl.sub.2 /MeOH = 15/1-8/1 4.96 102.5-104.0 (CHCl.sub.3)  4.00 g           (66.5)  3600, 3320, 1713,  (II-17)       (III-32)  1680, 1545,     1510,           1489 49 F(p) (VI-7) 2.25 g 25 4.08 2.65 105° C. 6     hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 2.78 118.0-119.0 (CHCl.sub.3)  2.30 g           (67.4)  3600, 3320, 1713,  (II-17)       (III-33)  1680, 1605,     1545,           1510, 1489 50 CF.sub.3 (m) (VI-1) 2.56 g 50 3.46 2.81     105-110° C. 9 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1-10/1 5.20     238.5-240.5 (Nujol)  Cl(p)       (92.9)  3350, 2650, 2525,  3.50 g     (III-34)  2450, 1720, 1677  (II-18)         1557 51 CF.sub.3 (m) (VI-7)     2.38 g 50 3.46 2.81 105-110 15 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1-10/1     4.75 255.0-257.0 (Nujol)  Cl(p)       (87.6)  3400, 3260, 2640,  3.50 g          (III-35)  2500, 2430, 1713,  (II-18)         1672, 1547      ##STR41##       52 2.80 g (VI-1) 2.64 g 36 4.46 2.90 105-110 8 days CH.sub.2 Cl.sub.2     /MeOH = 10/1 3.55 122.0˜123.0 (CHCl.sub.3)  (II-19)*.sup.1     (71.3)  3590, 3320, 1713,         (III-36)  1680, 1544, 1490,     1470, 1460(sh), 1450 53 2.10 g (VI-1) 1.70 g 30 1.73 2.50 105 7 days     CH.sub.2 Cl.sub.2 /MeOH = 10/1 3.00 -- (CHCl.sub.3)  (II-20)*.sup.2      (85.7)  3600, 3320, 1712,         (III-37)  1680, 1543 54 Cl(p) (VI-5)     1.03 g 10 1.63 1.06 90 12 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1-10/1 1.37     111.5-112.0 (CDCl.sub.3)  1.00 g       (74.0)  3600, 3280, 1702,     (II-21)       (III-38)  1698, 1530, 1645,           1495, 1480, 1463  55 C     l(p)2.0 g(II-21)      ##STR42##      25 3.26 2.12 90-95 10 hr. CH.sub.2 Cl.sub.2 /MeOH =      10/1 1.75(48.7)(III-39) 128.0-129.0 (CDCl.sub.3)3600, 3280, 1525,1492,     1480, 1460      56 t-Bu(p)1.00 g(II-6)     ##STR43##      10 K.sub.2 CO.sub.31.184 NaI0.96 100° C. 3 hr. CH.sub.2 Cl.sub.2     /MeOH/NH.sub.4 OH = 64/8/1 1.13(71.0)(III-40) -- (CHCl.sub.3)3590, 2498,     1510,1470, 1455, 1399  57 Me(p) (VI-9) 1.10 g 10 K.sub.2 CO.sub.3 NaI     100° C. 2.5 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH = 64/8/1     1.445 -- (CHCl.sub.3)  1.00 g   1.45 1.18   (83.6)  3580, 2498, 1510,     (II-8)       (III-41)  1463, 1450, 1375      58 tBu(p)0.81 g(II-6)     ##STR44##      12 K.sub.2 CO.sub.30.96 NaI0.78 100° C. 2.7 hr. CH.sub.2     Cl.sub.2 /MeOH/NH.sub.4 OH =      64/8/1 1.053(84.6)(III-42) -- (CHCl.sub.3)3580, 2498, 1510,1463, 1450,     1375      59 tBu(p)0.727 g(II-6)     ##STR45##      11 K.sub.2 CO.sub.30.86 NaI0.70 100°      C. 2.5 hr. -- 0.736(62.4)(III-43) -- (CHCl.sub.3)3630, 3590, 3390,2499,     1506, 1467,1440, 1421, 1399  60 Me(p) HO(CH.sub.2).sub.3 Cl (VI-12) --     Et.sub.3 N 140° C. 4.0 hr. CH.sub.2 Cl.sub.2 /MeOH = 9/1 8.51 g     183.0-185.0 (CHCl.sub.3)  10.2 g 5.81 ml  11.16 ml   (64.0)  3597, 3220,     1513,  (II-8)      (III-44)  1470, 1452, 1437,          1423, 1397 61     Me(p) (VI-3) 964 mg 15 K.sub.2 CO.sub.3 NaI 105° C. 5.75 hr.     CH.sub.2 Cl.sub.2 /MeOH = 9/1 0.74 g 170.0˜172.5 (CHCl.sub.3)     0.964 g   1.40 g 1.14 g  CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH = 64/8/1     (41.7)  3675, 3599, 3465,  (II-8)       (III-45)  3285, 2465, 1631,          1521, 1488, 1478,           1462, 1457(sh),           1439(sh),     1402 62 Ph(p) (VI-3) 0.70 g 11 K.sub.2 CO.sub.3 NaI 105° C. 5.75     hr. CH.sub.2 Cl.sub.2 /MeOH = 10/1 616 mg 225.0˜228.0 (Nujol)     0.93 g   1.02 g 0.83 g  CH.sub.2 Cl.sub.2 /MeOH/ (41.0) (dec.) 3300,     3055, 3030,  (II-5)      NH.sub.4 OH = 128/16/1 = 32/6/1 (III-46)  2810,     2770, 2670,           1606, 1528, 1487,           1471, 1456, 1448  63     CF.sub.3      (p)1.50 g(II-2)     ##STR46##      20 K.sub.2 CO.sub.31.69 g NaI1.38 mg 105° C. 8.0 hr. CH.sub.2     Cl.sub.2 /MeOH =      20/1-10/1 0.56 g(19.1)(III-47) 142.5-144.0 (CHCl.sub.3)3690, 3600,     1637(sh)1632, 1587, 1552,1510(sh), 1495, 1440            64 Me(p)1.44     g (II-8)      ##STR47##      CH.sub.2 Cl.sub.220 Et.sub.2 N1.16 ml room temperature92 hr. CH.sub.2     Cl.sub.2 /MeOH/NH.sub.4 OH = 128/10/1˜64/8/1 2.11 g(88.4)(III-48)     -- --       Exam. No. (II) R(CH.sub.2).sub.n Y (VI) DMF ml K.sub.2 CO.sub.3 g NaI     g reaction condition purification condition (1) g (%) (III) m.p.     (°C.)       65 (II-6) 3.67 g (VI-7) 3.00 g 45 4.35 3.54 105° C., 8 hr.     CH.sub.2 Cl.sub.2 /MeOH =      29/1˜9/1 4.90 (73.5) (III-49) 219.0˜222.0 66 (II-1) 3.60 g     (VI-7) 3.07 g 45 4.04 3.28 105° C., 9 hr. CH.sub.2 Cl.sub.2 /MeOH     = 10/1 5.57 (95.0) (III-50) 232.0˜239.0 67 (II-2) 4.70 g (VI-7)     3.34 g 45 4.83 3.93 105° C., 9 hr. CH.sub.2 Cl.sub.2 /MeOH =     15/1˜10/1 6.11 (87.4) (III-51) 266.0˜268.0 68 (II-16) 3.36 g      (VI-7) 2.50 g 35 3.62 2.95   105°  C., 12 hr. CH.sub.2 Cl.sub.2     /MeOH = 10/1 4.50 (83.7) (III-52) 230.0˜232.0 69 (II-5) 3.99 g     (VI-7) 3.00 g 45 4.35 3.54 105° C., 8 hr. CH.sub.2 Cl.sub.2 /MeOH     = 39/1˜19/1 5.61 (80.3) (III-53) 233.0˜238.0 70 (II-3) 3.45     g (VI-1) 3.00 g 45 4.35 3.54   105° C., 6.5 hr CH.sub.2 Cl.sub.2     /MeOH = 39/1˜9/1 5.34 (82.7) (III-54) 203.0˜207.5 71     (II-22)* 2.60 g  (VI-1) 2.23 g 30 3.01 2.44   105° C., 8.5 hr     CH.sub.2 Cl.sub.2 /MeOH =      10/1˜5/1 1.35 (30.5) (III-55) 95.0˜96.5     ##STR48##     ##STR49##     ##STR50##

                                      TABLE 8                                     __________________________________________________________________________    (Step 2)                                                                      (III)                      purification  Product                              (g)  acid  solvent (ml)                                                                         reflux time                                                                            condition (2) g (%)                                __________________________________________________________________________    (III-20)                                                                           TsOH.H.sub.2 O                                                                      toluene (60)                                                                         13 hr.   ethyl acetate Ia-36                                2.53 g                                                                             (2.68 g)                                                                            CH.sub.2 Cl.sub.2 (20)                                                                        CH.sub.2 Cl.sub.2 /MeOH = 10/1                                                              2.17 g                                                                        (90.3)                               (III-21)                                                                           TsOH.H.sub.2 O                                                                      toluene (300)                                                                        30 hr.   CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              Ia-37                                2.66 g                                                                             (2.93 g)                                                                            CH.sub.2 Cl.sub.2 (50)        2.27 g                                                                        (90.0)                               (III-22)                                                                           TsOH.H.sub.2 O                                                                      toluene (300)                                                                        48 hr.   ethyl acetate Ia-38                                3.30 g                                                                             (3.49 g)              CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              2.50 g                                                                        (80.0)                               (III-23)                                                                           TsOH.H.sub.2 O                                                                      toluene (250)                                                                        69 hr.   toluene/ethyl Ia-39                                3.18 g                                                                             (4.21 g)                                                                            CH.sub.2 Cl.sub.2 (60)                                                                        acetate = 1/1 2.96 g                                                          CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              (quantitative)                       (III-24)                                                                           CF.sub.3 COOH                                                                       --      8 hr.   toluene/ethyl Ia-40                                2.56 g                                                                             (27 ml)               acetate = 30/1                                                                              2.40 g                                                                        (98.0)                               (III-25)                                                                           CF.sub.3 COOH                                                                       --     8.5 hr.  CH.sub.2 Cl.sub.2 /MeOH = 30/1                                                              Ia-41                                3.80 g                                                                             (26 ml)                             3.50 g                                                                        (96.8)                               (III-26)                                                                           TsOH.H.sub.2 O                                                                      toluene (250)                                                                        27 hr.   CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              Ia-42                                3.16 g                                                                             (3.16 g)                                                                            CH.sub.2 Cl.sub.2 (70)        2.20 g                                                                        (73.1)                               (III-27)                                                                           TsOH.H.sub.2 O                                                                      toluene (200)                                                                        48 hr.   toluene/ethyl Ia-43                                2.45 g                                                                             (2.55 g)                                                                            CH.sub.2 Cl.sub.2 (50)                                                                        acetate = 1/1 1.87 g                                                          CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              (80.2)                               (III-28)                                                                           TsOH.H.sub.2 O                                                                      toluene (100)                                                                        29 hr.   CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              Ia-44                                2.10 g                                                                             (1.60 g)              ethyl acetate 1.480 g                                                                       (73.8)                               (III-29)                                                                           TsOH.H.sub.2 O                                                                      toluene (60)                                                                         31 hr.   CH.sub.2 Cl.sub.2 /MeOH = 15/1                                                              Ia-45                                0.84 g                                                                             (0.52 g)                            0.80 g                                                                        (quantitative)                       (III-30)                                                                           CF.sub.3 COOH                                                                       --     39 hr.   CH.sub.2 Cl.sub.2 /MeOH = 30/1                                                              Ia-46                                2.10 g                                                                             (10 ml)                             1.34 g                                                                        (70.2)                               (III-31)                                                                           CF.sub.3 COOH                                                                       --      8 hr.   CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              Ia-47                                3.51 g                                                                             (36 ml)                             2.80 g                                                                        (92.9)                               (III-32)                                                                           TsOH.H.sub.2 O                                                                      toluene (250)                                                                        26.5 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              Ia-48                                4.14 g                                                                             (3.25 g)                            3.16 g                                                                        (80.3)                               (III-33)                                                                           TsOH.H.sub.2 O                                                                      toluene (160)                                                                        16 hr.   CH.sub.2 Cl.sub.2 /MeOH = 15/1                                                              Ia-49                                1.93 g                                                                             (2.10 g)                                                                            CH.sub.2 Cl.sub.2 (60)        1.50 g                                                                        (81.9)                               (III-34)                                                                           CF.sub.3 COOH                                                                       --     25 hr.   CH.sub.2 Cl.sub.2 /MeOH =                                                                   Ia-50                                3.10 g                                                                             (35 ml)               30/1-20/1     2.80 g                                                                        (94.1)                               (III-35)                                                                           CF.sub.3 COOH                                                                       --     19.5 hr. CH.sub.2 Cl.sub.2 /MeOH =                                                                   Ia-51                                2.70 g                                                                             (35 ml)               50/1-20/1     2.40 g                                                                        (92.7)                               (III-36)                                                                           TsOH.H.sub.2 O                                                                      toluene (280)                                                                        26 hr.   toluene =     Ia-52                                4.09 g                                                                             (4.03 g)                                                                            CH.sub.2 Cl.sub.2 (70)                                                                        ethyl acetate = 3/1                                                                         3.76 g                                                          CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              (96.4)                               (III-37)                                                                           CF.sub.3 COOH                                                                       --      8 hr.   CH.sub.2 Cl.sub.2 /MeOH = 25/1                                                              Ia-53                                3.00 g                                                                             (30 ml)                             2.57 g                                                                        (89.5)                               (III-38)                                                                           TsOH.H.sub.2 O                                                                      benzene (150)                                                                        23 hr.   CH.sub.2 Cl.sub.2 /MeOH =                                                                   Ia-54                                2.86 g                                                                             (2.76 g)                                                                            CH.sub.2 Cl.sub.2 (50)                                                                        10/1-20/1     1.48 g                                                                        (48.7)                               (III-39)                                                                           TsOH.H.sub.2 O                                                                      benzene (150)                                                                        25 hr.   toluene/ethyl Ia-55                                1.00 g                                                                             (1.00 g)                                                                            toluene (100)   acetate = 1/1 0.93 g                                                          CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              (97.7)                               (III-40)                                                                           CF.sub.3 COOH                                                                              1.0 hr.  CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH                                                         Ia-56                                1.134 g                                                                            (10 ml)               64/8/1        1.416 g                                                                       (79.3)                               (III-41)                                                                           CF.sub.3 COOH                                                                              1.5 hr.  CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH                                                          Ia-57*                              1.445 g                                                                            (10 ml)               64/8/1        1.787 g                                                                       (75.1)                               (III-42)                                                                           CF.sub.3 COOH                                                                              50 min.  CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH                                                          Ia-58*                              1.002 g                                                                            (10 ml)               64/8/1        1.117 g                                                                       (69.8)                               (III-43)                                                                           CF.sub.3 COOH                                                                               1 hr.   CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH                                                          Ia-59*                              0.722 g                                                                             (6 ml)               128/12/1-64/8/1                                                                             0.881 g                                                                       (64.6)                               (III-44)                                                                           CF.sub.3 COOH                                                                              3.17 hr. CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH                                                         Ia-60                                12.82 g                                                                            (38.3 ml)             128/16/1-32/6/1                                                                             7.719 g                                                                       (64.9)                               (III-45)                                                                           CF.sub.3 COOH                                                                              1.5 hr.  CH.sub.2 Cl.sub.2 /MeOH/NH.sub.4 OH                                                          Ia-61*                              721 mg                                                                             (10 ml)               128/16/1      644 mg                                                                        (73.1)                               (III-46)                                                                           CF.sub.3 COOH                                                                               1 hr.   CH.sub.2 Cl.sub.2 /MeOH =                                                                    Ia-62*                              766 mg                                                                             (10 ml)               19/1˜9/1                                                                              572 mg                                                                        (60.5)                               (III-47)                                                                           CF.sub.3 COOH                                                                              48 hr.   CH.sub.2 Cl.sub.2 /MeOH =                                                                   Ia-63                                540 mg                                                                              (8 ml)               30/1˜10/1                                                                             529 mg                                                                        (69.2)                               (III-48)                                                                           CF.sub.3 COOH                                                                              1.25 hr. CH.sub.2 Cl.sub.2 /MeOH = 19/1                                                              Ia-64                                2.105 g                                                                             (5 ml)      room temperature       1.693 g                                                                       (85.3)                               (III-49)                                                                           CF.sub.3 COOH                                                                              50 min.  CH.sub.2 Cl.sub.2 /MeOH = 49/1                                                              Ia-65                                2.87 g                                                                             (35 ml)                             2.61 g                                                                        (86.7)                               (III-50)                                                                           CF.sub.3 COOH                                                                               8 hr.   CH.sub.2 Cl.sub.2 /MeOH =                                                                   Ia-66                                2.85 g                                                                             (30 ml)               20/1-10/1     2.70 g                                                                        (98.6)                               (III-51)                                                                           CF.sub.3 COOH                                                                              3 days.  CH.sub.2 Cl.sub.2 /MeOH =                                                                   Ia-67                                3.85 g                                                                             (50 ml)               15/1-10/1     3.53 g                                                                        (96.0)                               (III-52)                                                                           CF.sub.3 COOH                                                                               7 hr.   CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                              Ia-68                                1.75 g                                                                             (25 ml)                             1.54 g                                                                        (92.0)                               (III-53)                                                                           CF.sub.3 COOH                                                                              50 min.  CH.sub.2 Cl.sub.2 /MeOH = 49/1                                                              Ia-69                                2.98 g                                                                             (34 ml)                             2.71 g                                                                        (87.1)                               (III-54)                                                                           CF.sub.3 COOH                                                                              50 min.  toluene/acetone =                                                                           Ia-70                                2.62 g                                                                             (33 ml)               9/1-3/1       2.41 g                                                                        (87.5)                               (III-55)                                                                           CF.sub.3 COOH                                                                              2.5 hr.  CH.sub.2 Cl.sub.2 /MeOH =                                                                   Ia-71                                1.58 g                                                                             (20 ml)               15/1-7/1      1.28 g                                                                        (49.5)                               __________________________________________________________________________     *maleate                                                                 

                                      TABLE 9                                     __________________________________________________________________________    Compd.                                                                             m.p. (°C.)                                                                      Anal. Calcd. (%)                                                No.  (solvent*)                                                                             Found (%)  IR (cm.sup.-1)                                                                        NMR (δ)                                __________________________________________________________________________    Ia-36                                                                              130.5-132.0                                                                            C.sub.19 H.sub.25 N.sub.3 O.sub.2 :                                                      (CHCl.sub.3)                                                                          (CDCl.sub.3)                                      (CH.sub.2 Cl.sub.2 --                                                                  C, 69.42 (69.70)                                                                         3310, 1713, 1680                                                                      2.020(quint, J=8Hz, 2H); 2.329(s, 3H,                                         J=7Hz, 2H); 2.56-2.59(m,                          Et.sub.2 O)                                                                            H, 7.65 (7.70)                                                                           1545, 1489, 1460                                                                      4H); 2.671(t, J=7Hz, 2H); 2.766(t,                                            J=6Hz, 2H); 3.217(q,                                       N, 12.76 (12.83)   J=3Hz, 2H); 3.510(q, J=7Hz, 2H);                                              3.859(t, J=7Hz, 2H); 6.016                                                    (quint, J=3Hz, 1H); 7.116(d, J=8Hz, 2H);                                      7.284(d, J=8Hz, 2H);                                                          8.596(br, 1H)                                Ia-38                                                                              161.5-163.0                                                                            C.sub.22 H.sub.29 N.sub.3 O.sub.6 :                                                      (Nujol) (CDCl.sub.3)                                      (iPrOH)  C, 60.86 (61.24)                                                                         3330, 2600, 2500                                                                      1.782(quint, J-7Hz, 2H); 1.969(quint,                                         J=8Hz, 2H); 2.302(s, 3H);                         (oxalate)                                                                              H, 6.79 (6.77)                                                                           1717, 1645, 1605                                                                      2.44-2.59(m, 6H); 2.658(t, J=6Hz, 2H);                                        3.111(q, J=3Hz, 2H);                                       N, 9.51 (9.74)                                                                           1533, 1485, 1460                                                                      3.347(q, J= 7Hz, 2H); 3.813(t, J=7Hz,                                         2H); 5.999(quint, J=3Hz,                                                      1H); 6.00-7.02(m, 1H); 7.14-7.16(m, 3H);                                      8.456(brs, 1H)                               Ia-39                                                                              146.0-147.0                                                                            C.sub.22 H.sub.29 N.sub.3 O.sub.6 :                                                      (Nujol) (CDCl.sub.3)                                      (iPrOH)  C, 61.08 (61.24)                                                                         3300, 2600(br),                                                                       1.873(quint, J=7Hz, 2H); 2.030(quint,                                         J=8Hz, 2H); 2.297(s, 3H);                         (oxalate)                                                                              H, 6.70 (6.77)                                                                           1708, 1683, 1548                                                                      2.38-2.48(m, 2H); 2.593(t, J=7Hz, 2H);                                        2.606(t, J=8Hz, 2H);                                       N, 9.71 (9.74)                                                                           1490(sh), 1460                                                                        2.746(t, J=6Hz, 2H); 3.184(q, J=3Hz,                                          2H); 3.402(quint, J=7Hz,                                                      2H); 5.531(quint, J=2Hz, 1H);                                                 7.11-7.17(m, 4H); 8.519(brs, 1H)             Ia-40                                                                              146.5-147.5                                                                            C.sub.25 H.sub.33 N.sub.3 O.sub.6                                                        (Nujol) (CDCl.sub.3)                                      (iPrOH)  C, 63.40 (63.68)                                                                         3330, 2420-2300,                                                                      1.825(quint, J=8Hz, 2H); 2.020(quint,                                         J=7Hz, 2H); 2.240(s, 3H);                         (maleate)                                                                              H, 6.99 (7.05)                                                                           1700, 1620, 1575                                                                      2.254(s, 3H); 2.48-2.56(m, 4H); 2.594(t,                                      J=8Hz, 2H); 2.697(t,                                       N, 3.87 (8.91)                                                                           1530, 1460, 1450                                                                      J=5Hz, 2H); 3.147(q, J=3Hz, 2H);                                              3.390(q, J=7Hz, 2H); 3.859                                            (sh)    (t, J=7Hz, 2H); 6.002(quint, J=2Hz, 1H);                                      7.04-7.16(m, 3H);                                                             8.489(brs, 1H)                               Ia-41                                                                              159.0-160.0                                                                            C.sub.25 H.sub.33 N.sub.3 O.sub.6                                                        (Nujol) (CDCl.sub.3)                                      (iPrOH)  C, 63.71 (63.38)                                                                         3290, 2400-2300,                                                                      1.821(quint, J=7Hz, 2H); 2.013(quint,                                         J=8Hz, 2H); 2.300(s, 6H);                         (maleate)                                                                              H, 7.05 (7.05)                                                                           1720(sh), 1710,                                                                       2.48-2.55(m, 4H); 2.592(t, J=7Hz, 2H);                                        2.690(t, J=6Hz, 2H);                                       N, 8.86 (8.91)                                                                           1685, 1620, 1600                                                                      3.142(q, J=3Hz, 2H); 3.385(q, J=7Hz,                                          2H); 3.855(d-d, J.sub.1 =8Hz,                                         (sh), 1577, 1550                                                                      J.sub.2 =7Hz, 2H); 6.014(quint, J=2Hz,                                        1H); 6.878(s, 1H); 6.998(s,                                           1513    2H)                                          Ia-42                                                                              155.5-157.0                                                                            C.sub.23 H.sub.28 N.sub.3 O.sub.6 Cl                                                     (Nujol) (CDCl.sub.3)                                      (iPrOH)  C, 57.74 (57.80)                                                                         3310, 2350, 2260                                                                      1.825(quint, J=7Hz, 2H); 2.022(quint,                                         J=8Hz, 2H); 2.49-2.56(m,                          (maleate)                                                                              H, 5.84 (5.90)                                                                           1715, 1682, 1585                                                                      4H); 2.538(t, J=7Hz, 2H); 2.709(t,                                            J=6Hz); 3.159(q, J=3Hz,                                    N, 8.78 (8.79)                                                                           1520, 1485(sh),                                                                       2H); 3.389(q, J=7Hz, 2H); 3.861(t,                                            J=7Hz, 2H); 6.084(quint,                                   Cl, 7.14 (7.42)                                                                          1455    J=2Hz, 1H); 7.18-7.30(m, 3H); 7.346(s,                                        1H); 8.499(brs, 1H)                          Ia-43                                                                              102.0-103.5                                                                            C.sub.18 H.sub.22 N.sub.3 O.sub.2 Cl                                                     (CHCl.sub.3)                                                                          (CDCl.sub.3)                                      (ethyl   C, 61.99 (62.15)                                                                         3310, 1715, 1680                                                                      2.024(quint, J=7Hz, 2H); 2.55-2.64(m,                                         4H); 2.673(t, J=7Hz,                              acetate/ H, 6.31 (6.37)                                                                           1595, 1545, 1489                                                                      2H); 2.766(t, J=6Hz, 2H); 3.218(q,                                            J=3Hz, 2H); 3.504(q,                              Et.sub.2 O)                                                                            N, 12.07 (12.08)                                                                         1460    J=6Hz, 2H); 3.860(t, J=7Hz, 2H);                                              6.082(quint, J=2Hz, 1H);                                   Cl, 9.96 (10.19)   7.19-7.27(m, 3H); 7.361(s, 1H);                                               8.615(brs, 1H)                               Ia-44                                                                              140.5-142.0                                                                            C.sub.23 H.sub.28 N.sub.3 O.sub.5 Cl.                                                    (Nujol) (CDCl.sub.3)                                      (iPrOH)  1/5H.sub.2 O                                                                             3280, 2580, 2360                                                                      1.846(quint, J=7Hz, 2H); 2.048(quint,                                         J=8Hz, 2H); 2.47-2.51(m,                          (maleate)                                                                              C, 57.35 (57.37)                                                                         1715, 1690, 1620                                                                      2H); 2.566(t, J=8Hz, 2H); 2.606(t,                                            J=8Hz, 2H); 2.728(t, J=6Hz,                                H, 5.87 (5.94)                                                                           1580, 1545, 1490                                                                      2H); 3.172(q, J=3Hz, 2H); 3.397(q,                                            J=7Hz, 2H); 3.865(t,                                       N, 8.67 (8.37)                                                                           (sh), 1460                                                                            J=7Hz, 2H); 5.656(quint, J=2Hz);                                              7.15-7.37(m, 4H); 8.510                                    Cl, 7.72 (7.36)    (brs, 1H)                                    Ia-45                                                                              142.0-143.5                                                                            C.sub.22 H.sub.26 N.sub.3 O.sub.6 Cl                                                     (Nujol) (CDCl.sub.3)                                      (maleate)                                                                              C, 56.54 (56.96)                                                                         3300, 2580-2400,                                                                      2.007(t, quint, J=7Hz, 2H); 2.35-2.57(m,                                      2H); 2.610(t, J=8Hz);                                      H, 5.89 (5.65)                                                                           1710, 1682, 1617                                                                      2.746(t, J=7Hz, 2H); 2.830(t, J=6Hz,                                          2H); 3.723(q, J=3Hz,                                       N, 8.79 (9.06)                                                                           1565, 1528                                                                            2H); 3.544(q, J=6Hz, 2H); 3.869(t,                                            J=7Hz, 2H); 5.656(q,                                       Cl, 7.98 (7.64)    J=2Hz, 1H); 7.15-7.37(m, 4H); 8.626(brs,                                      1H)                                          Ia-46                                                                              216.0-217.5                                                                            C.sub.21 H.sub.25 N.sub.3 O.sub.6 Cl.sub.2.                                              (Nujol) (CDCl.sub.3)                                      (MeOH)   1/5H.sub.2 O                                                                             3340, 1710, 1645                                                                      1.807(quint, J=7Hz, 2H); 2.027(quint,                                         J=8Hz, 2H); 2.48-2.56(m,                          (oxalate)                                                                              C, 51.31 (51.48)                                                                         1588, 1562, 1538                                                                      4H); 2.599(t, J=8Hz, 2H); 2.689(t,                                            J=6Hz, 2H); 3.155(q,                                       H, 5.15 (5.23)                                                                           1488, 1460, 1420                                                                      J=3Hz, 2H); 3.383(q, J=7Hz, 2H);                                              3.859(t, J=7Hz, 2H); 6.111                                 N, 8.53 (8.58)     (quint, J=2Hz, 1H); 7.20-7.25(m, 3H);                                         8.510(brs, 1H)                                             Cl, 14.65(14.47)                                                Ia-47                                                                              99.0-100.0                                                                             C.sub.19 H.sub.24 N.sub.3 O.sub.2 Br:                                                    (CHCl.sub.3)                                                                          (CDCl.sub.3)                                      (CH.sub.2 Cl.sub.2 --                                                                  C, 56.32 (56.16)                                                                         3320, 1712, 1680                                                                      1.819(quint, J=7Hz, 2H); 2.023(quint,                                         J=7Hz, 2H); 2.49-2.56(m,                          Et.sub.2 O)                                                                            H, 6.04 (5.95)                                                                           1545, 1489, 1465                                                                      4H); 2.598(t, J=7Hz, 2H); 2.699(t,                                            J=6Hz, 2H); 3.145(q,                                       N, 10.35 (10.34)                                                                         (sh), 1460, 1440                                                                      J=3Hz, 2H); 3.386(q, J=6Hz, 2H);                                              3.861(t, J=7Hz, 2H); 6.064                                 Br, 19.59 (19.67)  (quint, J=2Hz, 1H); 7.247(d, J=8Hz, 2H);                                      7.462(d, J=8Hz,                                                               2H); 8.495(brs, 1H)                          Ia-48                                                                              97.5-98.5                                                                              C.sub.19 H.sub.24 N.sub.3 O.sub.2 F:                                                     (CHCl.sub.3)                                                                          (CDCl.sub.3)                                      (CH.sub.2 Cl.sub.2 --                                                                  C, 65.89 (66.07)                                                                         3320, 1713, 1682                                                                      1.825(quint, J=7Hz, 2H); 2.021(quint,                                         J-8Hz, 2H); 2.49-2.56(m,                          Et.sub.2 O)                                                                            H, 7.03 (7.00)                                                                           1605, 1545, 1510                                                                      4H); 2.597(t, J=8Hz, 2H); 2.705(t,                                            J=6Hz); 3.152(q, J=3Hz,                                    N, 12.07 (12.16)                                                                         1490, 1460                                                                            2H); 3.389(q, J=7Hz, 2H); 3.862(t,                                            J=7Hz, 2H); 5.998(quint,                                   F, 5.57 (5.50)     J=2Hz, 1H); 6.992(t, J=8Hz, 2H);                                              7.343(d-d, J.sub.1 =8Hz, J.sub.2 =5Hz,                                        2H); 8.495(brs, 1H)                          Ia-49                                                                              136.0-136.5                                                                            C.sub.22 H.sub.26 N.sub.3 O.sub.6 F:                                                     (Nujol) (CDCl.sub.3)                                      (iPrOH)  C, 59.13 (59.05)                                                                         3300, 2600(br)                                                                        2.028(quint, J=8Hz, 2H); 2.50-2.60(m,                                         4H); 2.674(t, J=7Hz,                              (maleate)                                                                              H, 5.85 (5.86)                                                                           1720, 1675, 1610                                                                      2H); 2.741(t, J=5Hz, 2H); 3.216(q,                                            J=3Hz, 2H); 3.551(q,                                       N, 9.31 (9.39)                                                                           1602, 1570, 1535                                                                      J=6Hz, 2H); 3.866(t, J=7Hz, 2H);                                              5.993(quint, J=2Hz, 1H);                                   F, 4.48 (4.25)                                                                           1515    6.997(t, J=9Hz, 2H); 7.350(d-d, J.sub.1                                       =9Hz, J.sub.2 =5Hz, 2H);                                                      8.615 (brs, 1H)                              Ia-50                                                                              185.0-188.0                                                                            C.sub.20 H.sub.23 N.sub.3 O.sub.2 ClF.sub.3.                                             (Nujol) (CDCl.sub.3)                                      (iPrOH--MeOH--                                                                         HCl.1/5H.sub.2 O                                                                         3320, 2670, 2550                                                                      1.822(quint, J=7Hz, 2H); 2.030(quint,                                         J=8Hz, 2H); 2.544(t,                              Et.sub.2 O)                                                                            C, 50.92 (51.11)                                                                         2420, 1710                                                                            J=8Hz, 2H); 2.55-2.60(m, 2H); 2.602(t,                                        J=8Hz, 2H); 2.718(t,                              (hydro-  H, 5.15 (5.23)     J=5Hz, 2H); 3.177(q, J=2Hz, 2H);                                              3.393(q, J=7Hz, 2H); 3.865                        chloride)                                                                              N, 8.71 (8.94)     (t, J=7Hz, 2H); 6.10-6.18(m, 1H);                                             7.40-7.50(m, 2H); 7.679                                    Cl, 14.95 (15.08)  (brs, 1H); 8.511(brs, 1H)                                  F, 11.83 (12.12)                                                Ia-51                                                                              213.0-215.0                                                                            C.sub.19 H.sub.21 N.sub.3 O.sub.2 ClF.sub.3.HCl                                          (Nujol) (CDCl.sub.3)                                      (iPrOH--MeOH)                                                                          C, 50.38 (50.45)                                                                         3500, 2520, 1704                                                                      2.030(quint, J=7Hz, 2H); 2.50-2.60(m,                                         2H); 2.597(t, J=8Hz,                              (hydro-  H, 4.90 (4.90)                                                                           1683, 1548, 1493                                                                      2H); 2.678(t, J=6Hz, 2H); 2.777(t,                                            J=6Hz, 2H); 3.236(q,                              chloride)                                                                              N, 9.22 (9.29)                                                                           1462    J=3Hz, 2H); 3.504(q, J=6Hz, 2H);                                              3.864(t, J=7Hz, 2H); 6.10-                                 Cl, 15.65 (15.68)  6.16(m, 1H); 7.40-7.50(m, 2H);                                                7.685(brs, 1H); 8.625(brs, 1H)                             F, 12.61 (12.60)                                                Ia-52                                                                              83.0-84.0                                                                              C.sub.17 H.sub.22 N.sub.3 O.sub.2 SCl                                                    (CHCl.sub.3)                                                                          (CDCl.sub.3)                                      (CH.sub.2 Cl.sub.2 --                                                                  C, 55.38 (55.50)                                                                         3320, 1712, 1680                                                                      1.801(quint, J=7Hz, 2H); 2.024(quint,                                         J=7Hz, 2H); 2.50(brs,                             Et.sub.2 O)                                                                            H, 5.96 (6.03)                                                                           1545    2H) 2.520(t, J=7Hz, 2H); 2.596(t, J=8Hz,                                      2H); 2.670(t, J=6Hz,                                       N, 11.51 (11.42)   2H); 3.119(q, J=3Hz, 2H); 3.376(q,                                            J=7Hz, 2H); 3.857(t,                                       S, 8.69 (8.71)     J=7Hz, 2H); 5.953(quint, J=2Hz, 1H);                                          6.688(d, J=4Hz, 1H);                                       Cl, 9.69 (9.64)    6.756(d, J=4Hz, 2H); 8.485(brs, 1H)          Ia-53                                                                              156.5-157.5                                                                            C.sub.21 H.sub.25 N.sub.3 O.sub.6 SCl.sub.2 :                                            (Nujol) (CDCl.sub.3)                                      (iPrOH)  C, 48.58 (48.65)                                                                         3300, 1708, 1680                                                                      1.808(quint, J=7Hz, 2H); 2.030(quint,                                         J=7Hz, 2H); 2.48-2.56(m,                          (maleate)                                                                              H, 4.89 (4.86)                                                                           1585, 1535                                                                            4H); 2.604(t, J=8Hz, 2H); 2.659(t,                                            J=6Hz, 2H); 3.136(q,                                       N, 8.02 (8.11)     J=3Hz, 2H); 3.383(q, J=7Hz, 2H);                                              3.862(t, J=7Hz, 2H); 5.995                                 S, 5.92 (6.18)     (quint, J=2Hz, 1H); 6.712(s, 1H);                                             8.497(brs, 1H)                               Ia-54                                                                              144.0-145.0                                                                            C.sub.24 H.sub.30 N.sub.3 O.sub.6 Cl                                                     (Nujol) (CDCl.sub.3)                                      (iPrOH)  C, 58.44 (58.59)                                                                         3280, 2400-2280,                                                                      1.78-1.91(m, 6H); 2.45-2.60(m, 6H);                                           2.703(t, J=6Hz, 2H); 3.161                        (maleate)                                                                              H, 6.05 (6.15)                                                                           1692, 1650, 1622                                                                      (q, J=3Hz, 2H); 3.383(q, J=7Hz, 2H);                                          3.76-3.83(m, 2H); 6.056                                    N, 8.52 (8.54)                                                                           1575, 1522, 1495                                                                      (quint, J=2Hz, 1H); 7.264, 7.322(ABq,                                         J=9Hz, 4H); 9.449                                          Cl, 7.33 (7.21)    (brs, 1H)                                    Ia-55                                                                              134.0-135.5                                                                            C.sub.19 H.sub.24 N.sub.3 O.sub.2 Cl                                                     (CHCl.sub.3)                                                                          (CDCl.sub.3)                                      (CH.sub.2 Cl.sub.2 --                                                                  C, 62.84 (63.06)                                                                         3280, 1795, 1645                                                                      1.78-1.85(m, 4H); 2.45-2.60(m, 4H);                                           2.680(t, J=7Hz, 2H); 2.770                        Et.sub.2 O)                                                                            H, 6.67 (6.68)                                                                           1527, 1495, 1480                                                                      (t, J=6Hz, 2H); 3.238(q, J=2Hz, 2H);                                          3.513(q, J=7Hz, 2H);                                       N, 11.41 (11.61)                                                                         1463, 1450                                                                            3.80-3.83(m, 2H); 6.051(quint, J=2Hz,                                         1H); 7.24-7.35(m, 4H);                                     Cl, 10.05 (9.80)   9.521(brs, 1H)                               Ia-56                                                                              192.5-193.5                                                                            C.sub.24 H.sub.38 N.sub.2.2C.sub.4 H.sub.4 O.sub.4                                       (Nujol) (CDCl.sub.3)(free)                                (CH.sub.2 Cl.sub.2 --                                                                  C, 65.32 (65.51)                                                                         2340, 1916, 1707                                                                      0.966(d, J=5Hz, 3H); 1.314(s, 9H);                                            1.43-1.57(m, 3H); 1.67-1.78                       MeOH--iPrOH)                                                                           H, 7.84 (7.90)                                                                           1619, 1563, 1542                                                                      (m, 2H); 1.930(quint, J=7Hz, 2H);                                             2.239(t, J=12Hz, 2H); 2.49-                       (di-maleate)                                                                           N, 4.77 (4.77)                                                                           1481, 1460, 1446                                                                      2.58(m, 2H); 2.528(t, J=7Hz, 2H);                                             2.63-2.74(m, 4H); 3.14-3.21                                           1378    (m, 4H); 6.027(quint, J=1Hz, 1H);                                             7.330(ABq, J=8Hz, 4H)                        Ia-57                                                                              191.5-193.0                                                                            C.sub.21 H.sub.32 N.sub.2.2C.sub.4 H.sub.4 O.sub.4                                       (Nujol) (CDCl.sub.3)                                      (CH.sub.2 Cl.sub.2 --                                                                  C, 63.75 (63.95)                                                                         2340, 1995, 1709                                                                      0.980(d, J=5Hz, 3H); 1.48-1.66(m, 3H);                                        1.70-1.82(m, 2H); 1.953                           MeOH--iPrOH)                                                                           H, 7.31 (7.40)                                                                           1621, 1525(sh),                                                                       (quint, J=7Hz, 2H); 2.333(s, 3H);                                             2.357(t, J=12Hz, 2H); 2.544                       (di-maleate)                                                                           N, 5.16 (5.14)                                                                           1510(sh), 1483,                                                                       (t, J=7Hz, 4H); 2.715(t, J=8Hz, 2H);                                          2.78-2.84(m, 2H); 3.160(q,                                            1462, 1449(sh),                                                                       J=3Hz, 2H); 3.298(d, J=12Hz);                                                 6.013(quint, J=1Hz, 1H);                                              1379    7.123, 7.284(ABq, J=8Hz, 4H)                 Ia-58                                                                              190.0-192.0                                                                            C.sub.23 H.sub.36 N.sub.2.2C.sub.4 H.sub.4 O.sub.4                                       (Nujol) (CDCl.sub.3)                                      (MeOH--iPrOH)                                                                          C, 64.92 (65.02)                                                                         2360, 1997, 1708                                                                      1.324(s, 9H); 1.50-2.00(m, 8H);                                               2.50-2.80(m, 12H); 3.200(q,                       (di-maleate)                                                                           H, 7.68 (7.74)                                                                           1619, 1570, 1535                                                                      J=3Hz, 2H); 6.056(s, 1H); 7.347(ABq,                                          J=8Hz, 4H)                                                 N, 4.91 (4.89)                                                                           1480, 1457, 1448                                                              (sh), 1379                                           Ia-59                                                                              193.0-195.0                                                                            C.sub.23 H.sub.37 N.sub.3.3C.sub.4 H.sub.4 O.sub.4                                       (Nujol) (CDCl.sub.3)                                      (CHCl.sub.3 --                                                                         C, 59.39 (59.58)                                                                         2335, 1995, 1706                                                                      1.313(s, 9H); 1.786(quint, J=7Hz, 2H);                                        2.296(s, 3H); 2.37-2.60                           MeOH)    H, 6.95 (7.03)                                                                           1621, 1568, 1542                                                                      (m, 17H); 2.703(t, J=5Hz, 2H); 3.158(q,                                       J=3Hz, 2H); 6.028                                 (tri-maleate)                                                                          N, 6.01 (5.96)                                                                           (sh), 1478, 1460                                                                      (quint, J=1Hz, 1H); 7.382(ABq, J=8Hz,                                         4H)                                                                   1439, 1380(sh)                                       Ia-60                                                                              75.0-77.0                                                                              C.sub.16 H.sub.21 NO                                                                     (Nujol) (CDCl.sub.3)                                      (Et.sub.2 O-                                                                           C, 77.94 (77.88)                                                                         3110, 3023, 2773                                                                      1.791(quint, J=7Hz, 2H); 2.332(s, 3H);                                        2.50-2.60(m, 2H); 2.735                           n-hexane)                                                                              H, 9.16 (9.15)                                                                           1518, 1467, 1412                                                                      (t, J=6Hz, 2H); 2.775(t, J=6Hz, 2H);                                          3.221(q, J=3Hz, 2H);                                       N, 6.22 (6.05)                                                                           1397, 1379                                                                            3.834(t, J=5Hz, 2H); 6.001(quint, J=2Hz,                                      1H); 7.123, 7.272                                                             (ABq, J=8Hz, 4H)                             Ia-61                                                                              115.0-116.0                                                                            C.sub.20 H.sub.39 N.sub.3 O.C.sub.4 H.sub.4 O.sub.4                                      (Nujol) (CD.sub.3 OD)                                     (iPrOH--Et.sub.2 O)                                                                    C, 64.88 (64.99)                                                                         3405, 2720, 2570                                                                      1.87-12.05(m, 6H); 2.333(s, 3H);                                              2.886(brs, 2H); 3.21-3.36(m,                      (maleate)                                                                              H, 7.54 (7.50)                                                                           2295, 1642, 1580                                                                      1H); 3.522(brs, 2H); 3.913(s, 2H);                                            6.099(s, 1H); 6.245(s, 2H);                                N, 9.42 (9.47)                                                                           1538, 1499, 1457                                                                      7.188, 7.369(ABq, J=9Hz, 4H)                                          1411, 1380                                           Ia-62                                                                              164.0-166.0                                                                            C.sub.25 H.sub.31 N.sub.3 O.C.sub.4 H.sub.4 O.sub.4                                      (Nujol) (CD.sub.3 OD)                                     (MeOH--Et.sub.2 O)                                                                     C, 68.89 (68.89)                                                                         3403, 3037, 2330                                                                      1.88-2.06(m, 4H); 2.951(brs, 2H);                                             3.20-3.40(m, 6H); 3.557(brs,                      (maleate)                                                                              H, 6.97 (6.98)                                                                           1700, 1640, 1578                                                                      2H); 3.959(brs, 2H); 6.220(s, 1H);                                            6.248(s, 2H); 7.30-7.70(m,                                 N, 8.30 (8.31)                                                                           1537, 1498, 1457                                                                      9H)                                                                   (sh), 1449, 1409                                     Ia-63                                                                              150.0-151.5                                                                            C.sub.24 H.sub.28 N.sub.5 OF.sub.3                                                       (CHCl.sub.3)                                                                          (CDCl.sub. 3)                                     (CH.sub.2 Cl.sub.2 --                                                                  C, 62.55 (62.73)                                                                         1632, 1617(sh),                                                                       1.940(quint, J=7Hz, 2H); 2.450(t, J=8Hz,                                      2H); 2.547(t,                                     Et.sub.2 O)                                                                            H, 6.08 (6.14)                                                                           1588, 1552, 1495                                                                      J=7Hz, 2H); 5.565(brs, 2H); 2.727(t,                                          J=6Hz, 2H); 6.142(s,                                       N, 15.13 (15.24)                                                                         1437    1H); 6.515(t, J=5Hz, 1H); 7.448,                                              7.540(ABq, J=8Hz, 4H); 8.301                               F, 12.36 (12.40)   (d, J=5Hz, 2H)                               Ia-64                                                                              108.0-109.0                                                                            C.sub.19 H.sub.26 N.sub.2 O                                                              (CHCl.sub.3)                                                                          (CDCl.sub.3)                                      (CH.sub.2 Cl.sub.2 --                                                                  C, 76.26 (76.47)                                                                         1625, 1512, 1466                                                                      1.78-2.04(m, 4H); 2.332(s, 3H); 2.574(t,                                      J=8Hz, 4H); 2.765(t,                              Et.sub.2 O-                                                                            H, 8.70 (8.78)                                                                           1448, 1378                                                                            J=6Hz, 2H); 2.881(t, J=8Hz, 2H);                                              3.211(q, J=3Hz, 2H); 3.448                        n-hexane)                                                                              N, 9.32 (9.39)     (t, J=6Hz, 2H); 3.477(t, J=6Hz, 2H);                                          6.02(quint, J=2Hz, 1H);                                                       7.122, 7.285(ABq, J=8Hz, 4H)                 Ia-65                                                                              183.0-190.0                                                                            C.sub.22 H.sub.31 N.sub.3 O.sub.2.HCl                                                    (Nujol) (CDCl.sub.3)                                      (MeOH--Et.sub.2 O)                                                                     C, 65.06 (65.09)                                                                         3310, 2725, 2670                                                                      1.313(s, 9H); 2.018(quint, J=8Hz, 2H);                                        2.52-2.64(m, 6H); 2.678                           (hydro-  H, 8.04 (7.95)                                                                           2405, 1709, 1688                                                                      (t, J=7Hz, 2H); 2.774(t, J=6Hz, 2H);                                          3.212, 3.242(ABq,                                 chloride)                                                                              N, 10.38 (10.35)                                                                         1549, 1519, 1488                                                                      J=3Hz, 2H) 3.545, 3.484(ABq, J=7Hz, 2H);                                      3.859(t, J=7Hz,                                            Cl, 8.46 (8.73)                                                                          1459, 1430, 1412                                                                      2H); 6.029(quint, J=2Hz, 1H); 7.332(s,                                        4H); 8.604(brs, 1H)                                                   1392                                                 Ia-66                                                                              216.0-219.0                                                                            C.sub.18 H.sub.21 N.sub.3 O.sub.2 Cl.sub.2.HCl                                           (Nujol) (CDCl.sub.3)                                      (MeOH--Et.sub.2 O)                                                                     C, 51.66 (51.63)                                                                         3290, 2510, 1712                                                                      2.024(quint, J=7Hz, 2H); 2.45-2.55(m,                                         2H); 2.594(t, J=8Hz,                              (hydro-  H, 5.34 (5.30)                                                                           1672, 1521                                                                            2H); 2.665(t, J=7Hz, 2H); 2.754(t,                                            J=6Hz, 2H); 3.214(q,                              chloride)                                                                              N, 10.01 (10.03)   J=3Hz, 2H); 3.497(q, J=6Hz, 2H);                                              3.860(t, J=7Hz, 2H); 6.0-                                  Cl, 25.12 (25.40)  6.14(m, 1H); 7.208(dd, J.sub.1 =8Hz,                                          J.sub.2 =2Hz, 1H); 7.365(d, J=8Hz,                                            1H); 7.450(d, J=2Hz, 1H); 8.615(brs,                                          1H)                                          Ia-67                                                                              238.0-248.0                                                                            C.sub.19 H.sub.22 N.sub.3 O.sub.2 F.sub.3.HCl                                            (Nujol) (CDCl.sub.3)                                      (MeOH--Et.sub.2 O)                                                                     C, 54.43 (54.61)                                                                         3310, 2930, 2860                                                                      2.032(quint, J=8Hz, 2H); 2.50-2.66(m,                                         4H); 2.69(t, J=6Hz, 2H);                          (hydro-  H, 5.59 (5.55)                                                                           2460, 1711, 1687                                                                      2.722(t, J=6Hz, 2H); 3.256(q, J=3Hz,                                          2H); 3.518(q, J=6Hz,                              chloride)                                                                              N, 9.89 (10.06)                                                                          1617, 1541                                                                            2H); 3.868(t, J=7Hz, 2H); 6.14-6.17(m,                                        1H); 7.478, 7.567(ABq,                                     Cl, 8.45 (8.48)    J=9Hz, 4H); 8.625(brs, 1H)                                 F, 13.68 (13.64)                                                Ia-68                                                                              228.0-232.0                                                                            C.sub.18 H.sub.22 N.sub.3 O.sub.2 Br.HCl                                                 (Nujol) (CD.sub.3 OD)                                     (MeOH--Et.sub.2 O)                                                                     C, 50.89 (50.42)                                                                         3320, 2920, 2860                                                                      2.029(quint, J=8Hz, 2H); 2.50-2.60(m,                                         2H); 2.598(t, J=8Hz,                              (hydro-  H, 5.58 (5.41)                                                                           2460, 1710, 1685                                                                      2H); 2.675(t, J=7Hz, 2H); 2.769(t,                                            J=6Hz, 2H); 3.216(q,                              chloride)                                                                              N, 9.90 (9.80)                                                                           1537    J=3Hz, 2H); 3.509(q, J=6Hz, 2H);                                              3.865(t, J=7Hz, 2H); 6.04-                                 Cl, 8.22 (8.27)    6.08(m, 1H); 7.429, 7.247(ABq, J=9Hz,                                         4H); 8.611(brs, 1H)                          Ia-69                                                                              205.0-210.0                                                                            C.sub.24 H.sub.27 N.sub.3 O.sub.2.HCl                                                    (Nujol) (CDCl.sub.3)                                      (MeOH--Et.sub.2 O)                                                                     C, 67.72 (67.67)                                                                         3305, 3045, 2415                                                                      2.205(quint, J=8Hz, 2H); 2.54-2.66(m,                                         4H); 2.695(t, J=7Hz,                              (hydro-  H, 6.64 (6.63)                                                                           2405, 1702, 1679                                                                      2H); 2.803(t, J=6Hz, 2H); 3.261(q,                                            J=3Hz, 2H); 3.558, 3.497                          chloride)                                                                              N, 9.80 (9.87)                                                                           1578, 1540, 1488                                                                      (ABq, J=7Hz, 2H); 3.865(t, J=7Hz, 2H);                                        6.128(quint, J=2Hz,                                        Cl, 8.10 (8.32)                                                                          1457, 1444, 1420                                                                      1H); 7.28-7.67(m, 9H); 8.624(brs, 1H)                                 1392                                                 __________________________________________________________________________     *a solvent for recrystallization                                         

EXAMPLE 721-{3-(1-Methyl-2-oxo-imidazolidin-1-yl)propyl}-4-(4-tolyl)-1,2,5,6-tetrahydropyridine(Ia-72) ##STR51##

(1) A mixture of 870 mg of the compound (Ia-60) and 8.0 ml ofthionylchloride is stirred at room temperature for 2 hours. Afterremoval of the excess reagent under reduced pressure, the residue waswashed with Et₂ O and dried under reduced pressure to prepare 1.067 g(Yield: 99.2%) of the compound (V-3) as pale yellow powder.

IR (CHCl₃) cm⁻¹ : 1600, 1510, 1460, 1410.

NMR (CDCl₃): 2.046 (quint, J=7 Hz, 2H); 2.334 (s, 3H); 2.54-2.64 (m,2H); 2.629 (t, J=7H, 2H); 2.273 (t, J=5 Hz, 2H); 3.173 (q, J=2 Hz, 2H);3.630 (t, J=7 Hz, 2H); 6.023 (quint, J=2 Hz, 1H); 7.123, 7.287 (ABq, J=8Hz, 4H).

(2) To a solution of 266 mg of 1-methyl-2-oxoimidazolidine in 5 ml ofDMF was added 115 mg of 60% NaH under ice-cooling. After stirring atroom temperature for 20 minutes, a solution of 553 mg of the compound(V-3) in 4 ml of DMF was added to the reaction mixture and stirred atroom temperature for 90.5 hours. The reaction mixture was concentratedunder reduced pressure and poured into d-HCl. The aqueous layer is madealkaline with NaHCO₃, extracted with CHCl₃ -MeOH (19/1), dried overMgSO₄, and evaporated. The residue is subjected to column chromatographywith silica gel, eluting with CHCl₃ -MeOH (19/1) to prepare 491 mg ofthe compound (Ia-72). The maleate is recrystallized from iPrOH-Et₂ O toprepare 439 mg (Yield: 45.8%) of colorless needles. mp. 126.5°-128.0° C.

Anal Calcd. (%) for C₁₉ H₂₇ N₃ O.C₄ H₄ O₄. 1/5H₂ O: C, 63.73; H, 7.20;N, 9.61. Found: C, 63.78; H, 7.31; N, 9.70.

IR (CHCl₃): 2450, 2340, 1910, 1689, 1622, 1502, 1451, 1409, 1382.

NMR (CDCl₃): 1.797 (quint, J=8 Hz, 2H); 2.329 (s, 3H); 2.46-2.62 (m,4H); 2.712 (t, J=5 Hz, 2H); 2.790 (s, 3H); 3.166 (q, J=3 Hz, 2H); 3.255(t, J=7 Hz, 2H); 3.295 (s, 4H); 6.014 (quint, J=2 Hz, 1H); 7.117, 7.283(ABq, J=8 Hz, 4H).

EXAMPLE 73-91

The compounds (V) obtained in Example 19-21 are reacted in the samemanner as Example 72 to prepare the compound (Ia). The reactionconditions are shown in Table 10.

                                      TABLE 10                                    __________________________________________________________________________     ##STR52##                                                                    Ex.                       reaction                                                                             purification                                                                            product                            No.                                                                              (V) (VIII)      solvent                                                                              condition                                                                            condition mg (Yield)                                                                          m.p. (°C.)                                                                   IR                     __________________________________________________________________________    73 (V-3) 742 mg                                                                       ##STR53##  DMF 5 ml                                                                             100° C. 47 min.                                                               CH.sub.2 Cl.sub.2 /MeOH= 19/1                                                           Ia-73*.sup.1 602                                                                    119.0- 121.0 (iPrOH)                                                                (CHCl.sub.3) 2455,                                                            2310, 1677 1622,                                                              1512, 1497 1464,                                                              1380, 1351             74 (V-2) 1.02 g                                                                       ##STR54##  DMF 10 ml                                                                            100° C. 25 hr.                                                                toluene/ acetone=3/1-1/1                                                                Ia-74*.sup.1 266                                                                    152.0- 154.0 (MeOH                                                            Et.sub.2 O)                                                                         (Nujol) 2700-1750(b                                                           r), 1695, 1663,                                                               1619 1532, 1463,                                                              1412 1378, 1358        75 (V-3) 500 mg                                                                       ##STR55##  DMF 8 ml                                                                             70° C. 10 hr.                                                                 CH.sub.2 Cl.sub.2 /MeOH= 39/1                                                           Ia-75 409 mg (62.4%)                                                                98.0-100.0 (CDCl.sub.3                                                        MeOH) (CHCl.sub.3) 3690,                                                            1771, 1602 1511,                                                              1488, 1454 1429,                                                              1416, 1384             76 (V-3)                                                                             H.sub.2 NPh 0.192 ml                                                                      DMF 8 ml                                                                             80° C.                                                                        toluene/  Ia-76*.sup.1                                                                        154.0-                                                                              (Nujol)                   500 mg                                                                            (K.sub.2 CO.sub.3 576 mg                                                                         15 hr. acetone = 4/1                                                                           130 mg                                                                              155.5 3050, 2660, 2615              NaI 468 mg                          (72.1%)                                                                             (MeOH 2570, 2480, 2410              Pyridine 178 ml)                          Et.sub.2 O)                                                                         1606, 1590, 1578                                                              1517, 1498, 1479                                                              1447, 1423, 1398                                                              1376                   77 (V-3) 650 mg                                                                       ##STR56##  DMF 6 ml                                                                             100° C. 5 hr.                                                                 toluene/ acetone = 9/1                                                                  Ia-77*.sup.1 1.08                                                                   174.0- 176.0 (dec.)                                                           (MeOH Et.sub.2 O)                                                                   (CHCl.sub.3) 3685,                                                            3495, 3350                                                                    2700-1800(br),                                                                1778, 1707, 1621                                                              1511, 1496, 1446                                                              1395                   78 (V-2)                                                                             CH.sub.3 NHPh 0.20 ml                                                                     DMF 8 ml                                                                             110° C.                                                                       toluene/  Ia-78*.sup.1                                                                        149.0-                                                                              (CHCl.sub.3)              440 mg                                                                            (Pyridine 0.157 ml 6 hr. 20 min.                                                                        acetone = 9/1                                                                           135 mg                                                                              151.0 3575, 3338                    NaI 412 mg)                         (17.6%)                                                                             (MeOH                                                                         Et.sub.2 O)                  79 (V-3)                                                                             NaOPh 207 mg                                                                              DMF 8 ml                                                                             70° C.                                                                        toluene/  Ia-79*.sup.1                                                                        148.0-                                                                              (Nujol)                   0.828 g                3 hr. 10 min.                                                                        acetone = 9/1                                                                           562 mg                                                                              150.0 2720, 2370, 1701                                                  (66.3%)                                                                             (MeOH 1620, 1598, 1584                                                        Et.sub.2 O                                                                          1499, 1467,                                                             iPrOH 1458(sh), 1387         80 (V-3) 942 mg                                                                       ##STR57##  --     150° C. 8 hr. 15 min.                                                         toluene/ acetone =  19/1-9/1                                                            Ia-80*.sup.1 930                                                                    148.0-150.0 (iPrOH                                                            Et.sub.2 O)                                                                         (Nujol) 2720,                                                                 2575(sh), 2490(sh),                                                            2330, 1708, 1652,                                                            1600 1571, 1502,                                                              1459                   81 (V-3) 624 mg                                                                       ##STR58##  --     150° C. 4 hr. 10 min.                                                         CH.sub.2 Cl.sub.2 /MeOH= 19/1                                                           Ia-81*.sup.1 963                                                                    191.0-  192.0 (dec.)                                                          (MeOH Et.sub.2 O)                                                                   (Nujol) 3030,                                                                 2720, 2278 1711,                                                              1623, 1572 1532,                                                              1513(sh), 1485,                                                               1463, 1435             82 (V-3)                                                                             HN(iBu).sub.2 1.358 g                                                                     --     20 hr. CH.sub.2 Cl.sub.2 /MeOH=                                                                Ia-82*.sup.1                                                                        140.5-                                                                              (Nujol)                   517 mg                 reflux 49/1      457 mg                                                                              142.5 2710, 2500, 1706                                                  (38.4%)                                                                             (CH.sub.2 Cl.sub.2                                                                  1572, 1480, 1455                                                        Et.sub.2 O)                                                                         1375                   83 (V-3)                                                                             H.sub.2 N(iBu) 1.02 ml                                                                    --     10.5 hr.                                                                             CH.sub.2 Cl.sub.2 /MeOH/                                                                Ia-83*.sup.1                                                                        179.5-                                                                              (Nujol)                   511 mg                 reflux NH.sub.4 OH=                                                                            471 mg                                                                              182.5 3340, 2780, 2545                                        128/12/1  (44.4%)                                                                             (CH.sub.2 Cl.sub.2                                                                  2460, 1699, 1618                                                        Et.sub.2 O)                                                                         1577, 1474, 1458                                                              1441, 1381             84 (V-3) 466 mg                                                                       ##STR59##  --     50° C. 3 hr.                                                                  CH.sub.2 Cl.sub.2 /MeOH/ NH.sub.4 OH=                                         128/16/1- 32/4/0.5                                                                      Ia-84*.sup.1 225                                                                    180.0- 181.0                                                                        (Nujol) 2340,                                                                 1709, 1550 1458,                                                              1377, 156              85 (V-3)                                                                             H.sub.2 N(CH.sub.2).sub.2 N(iPr).sub.2                                                    --     105° C.                                                                       CH.sub.2 Cl.sub.2 /MeOH/                                                                Ia-85*.sup.1                                                                        125.0-                                                                              (Nujol)                   511 mg                                                                            1.054 g            7 hr.  NH.sub.4 OH=                                                                            436 mg                                                                              127.0 2668, 2500, 2400                                        128/16/1- (32.0%)     (sh), 1702, 1619                                        64/8/1                1570, 1462, 1378       86 (V-2)                                                                             HN(iBu).sub.2 1.50 g                                                                      --     32 hr. CH.sub.2 Cl.sub.2 /MeOH=                                                                Ia-86*.sup.1                                                                        135.0-                                                                              (Nujol)                   654 mg                 reflux 49/1-19/1 338 mg                                                                              136.5 2420, 1707, 1616                                                  (27.1%)     1572, 1485, 1456                                                              1377                   87 (V-2)                                                                             HN(iBu).sub.2 1.1 ml                                                                      --     32 hr. CH.sub.2 Cl.sub.2 /MeOH=                                                                Ia-87*.sup.1                                                                        135.0-                                                                              (Nujol)                   645 mg                 reflux 49/1-19/1 338 mg                                                                              136.0 2420, 1707, 1616                                                  (27.1%)                                                                             (MeOH 1572, 1485, 1456                                                        Et.sub.2 O)                                                                         1377                   88 (V-2) 1.05 g                                                                       ##STR60##  --     room temperature 32.5 hr.                                                            CH.sub.2 Cl.sub.2 /MeOH/ NH.sub.4 OH=                                         128/16/1- 32/4/0.5                                                                      Ia-88*.sup.1 1.034                                                                  176.0- 178.0 (MeOH)                                                                 (Nujol) 3483,                                                                 2723, 2679 2587,                                                              2415, 1703 1608,                                                              1579, 1478 1460,                                                              1412, 1382             89 (V-2) 621 mg                                                                       ##STR61##  --     room temperature 5 days                                                              CH.sub.2 Cl.sub.2 /MeOH/ NH.sub.4 OH=                                         128/16/1  Ia-89*.sup.1 800                                                                    190- 191.0 (dec.)                                                                   (Nujol) 2355,                                                                 1711, 1620 1577,                                                              1543, 1479 (sh),                                                              1461, 1378             90 (V-1) 828 mg                                                                       ##STR62##  --     150° C. 3 hr.                                                                 CH.sub.2 Cl.sub.2 /MeOH= 29/1-19/1                                                      Ia-90*.sup.1 1.025                                                                  183.5- 185.0 (CHCl.sub.                                                       3 MeOH)                                                                             (Nujol) 2340,                                                                 1708, 1619 1568,                                                              1528(sh), 1485,                                                               1461                   91 (V-1)                                                                             HN(iBu).sub.2 3.76 ml                                                                     --     33 hr. CH.sub.2 Cl.sub.2 /MeOH=                                                                Ia-91*.sup.1                                                                        176.5-                                                                              (Nujol)                   628 mg                 reflux 49/1-19/1 685 mg                                                                              178.0 2620, 2510, 1690                                                  (51.6%)                                                                             (dec.)                                                                              1657, 1618, 1579                                                        (MeOH 1533, 1488, 1460                                                        Et.sub.2 O)                                                                         1409,                  __________________________________________________________________________                                                           1378                    *.sup.1 maleate                                                          

EXAMPLE 924-(4-tert-Butylphenyl)-1-[3-{4-(pyrimidin-2-yl)piperazin-1-yl}propyl]-1,2,5,6-tetrahydropyridine(Ia-92) ##STR63##

(1) A mixture of 1.1 g of3-{4-(pyrimidin-2-yl)piperazin-1-yl)propylchloride, 1.07 g of thecompound (II-6), 1.26 g of K₂ CO₃, and 1.03 g of NaI in 12 ml of DMF isstirred at 100° C. for 4 hours. The reaction mixture is poured intoice-water and extracted with ethyl acetate. The organic layer is washedwith water, dried and evaporated. The residue is purified by silica gelchromatography (CH₂ Cl₂ /MeOH=10/1) followed by recrystallization fromCH₂ Cl₂ -Et₂ O to prepare 1.70 g (Yield: 85%) of the compound (III-56).mp. 215.0°-225.0° C. (dec.)

(2) A solution of 1.58 g of the compound (III-56) in 15 ml of CF₃ COOHis refluxed for 3.5 hours. After removal of the excess reagent, theresidue is poured into ice-cooled aq.NaHCO₃ and extracted. The organiclayer is dried over Na₂ SO₄ and evaporated under reduced pressure. Theoily residue is purified by column chromatography with silica gel,eluting with CH₂ Cl₂ /MeOH (10/1-5/1) to prepare 1.44 g (Yield: 95%) ofthe compound (Ia-92) as crystals (mp. 79.0°-81.0° C.). The maleate isrecrystallized from methanol to prepare colorless needles. mp.209.0°-211.0° C. (dec.).

EXAMPLE 93-94

The reactions are performed in the same manner as Example 92 to preparethe compound (III) and (Ia). The reaction conditions and physicalconstants are shown in Tables 11 and 12.

                                      TABLE 11                                    __________________________________________________________________________    (Step 1)                                                                       ##STR64##                                                                    Ex.                 DMF K.sub.2 CO.sub.3                                                                  NaI                                                                              reaction                                                                             purification                                                                            g (Yield)                     No.                                                                              (II)                                                                              R(CH.sub.2)nY (VI)                                                                         (ml)                                                                              (g) (g)                                                                              condition (1)                                                                        condition (1)                                                                           Compd. No.                                                                          m.p.                    __________________________________________________________________________                                                          (°C.)            93 (II-6) 980 mg                                                                      ##STR65##   20  1.16                                                                              0.94                                                                             105 6.5 hr.                                                                          CH.sub. 2 Cl.sub.2 /MeOH                                                                1.69 (92.6) (III-57)                                                                129.0-130.5                                                                   (CH.sub.2 Cl.sub.2Et                                                          .sub.2 O) (maleate)     94 (II-6) 2.67 g                                                                      ##STR66##   20  3.18                                                                              2.60                                                                             95-100 CH.sub.2 Cl.sub.2 /MeOH                                                                 4.04 (93.3) (III-58)                                                                137.0-138.5                                                                   (CH.sub.2 Cl.sub.2Et                                                          .sub.2 O) (maleate)     __________________________________________________________________________

                                      TABLE 12                                    __________________________________________________________________________    (Step 2)                                                                      (III)            purification                                                                              (I .sup.a)                                       (g)  CF.sub.3 COOH                                                                       reflux time                                                                         condition   g (Yield)                                                                          m.p. (°C.)                                                                   IR                                    __________________________________________________________________________    (III-57)                                                                           20 ml 4 hr. CH.sub.2 Cl.sub.2 /MeOH =                                                                 Ia-93                                                                              105-106                                                                             (Nujol)                               1.50 g           20/1- 10/1  1.40 g                                                                             (MeOH)                                                                              1710, 1622, 1598, 1575,                                            (97.4)     1495 (sh), 1480, 1462,                                                        1450, 1385, 1360                      (III-58)                                                                           10 ml 8 hr. CH.sub.2 Cl.sub.2 /MeOH = 20/1                                                            Ia-94                                                                              213.0-                                                                              (Nujol)                               0.88 g                       maleate                                                                            214.5 2300, 1717, 1622, 1575,                                            0.74 g                                                                             (MeOH)                                                                              1535, 1500, 1465, 1458,                                            (97.5)     1450                                  __________________________________________________________________________

EXAMPLE 954-(4-Hydroxyphenyl)-1-{3-(4-morpholinyl)propyl}-1,2,5,6-tetrahydropyridine(Ia-95) ##STR67##

(1) A mixture of 2.829 g of 4-(4-methoxyphenyl)-4-hydroxypiperidine,2.02 ml of 3-bromopropylchloride, and 3.773 g of K₂ CO₃ in 30 ml of DMFis stirred at room temperature for 3 hours. The reaction mixture ispoured into ice-water and extracted with ethyl acetate. The organiclayer is dried and evaporated under reduced pressure to prepare 4.525 gof pale yellow solid. Purification is conducted by column chromatographywith silica gel, eluting with CH₂ Cl₂ /MeOH (29/1-5/1) to prepare 3.316g (Yield: 85.6%) of the compound (IV-8) as solid which is recrystallizedfrom n-hexane-Et₂ O to prepare colorless needles. mp. 103.5°-105.0° C.

Anal Calcd. (%) for C₁₅ H₂₂ ClNO₂ : C, 63.48; H, 7.81; N, 4.94; Cl,12.49. Found: C, 63.47; H, 7.78; N, 5.01; Cl,12.45.

IR (CHCl₃): 3595, 1610, 1582, 1510, 1468, 1462, 1454, 1441, 1375.

NMR (CDCl₃) δ:1.761 (d-d, J₁ =14 Hz, J₂ =3 Hz, 2H); 1.998 (quint, J=7Hz, 2H); 2.121 (t-d, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.475 (t-d, J₁ =12 Hz, J₂=3 Hz, 2H); 2.560 (t, J=7 Hz, 2H); 2.782 (d-d, J₁ =14 Hz, J₂ =3 Hz, 2H);3.618 (t, J=7 Hz, 2H); 3.805 (s, 3H); 6.886, 7427 (ABq, J=9 Hz, 4H).

(2) To a solution of 3.176 g of the compound (IV-8) is added 3.17 ml ofBBr₃ with stirring under ice-cooling. After refluxing for 1.5 hours, thereaction mixture is poured into ice-water and the aqueous layer is madealkaline with c.NH₄ OH and extracted with CH₂ Cl₂ /MeOH (4/1). Theorganic layer is dried and evaporated to dryness. The crude product isdissolved in 20 ml of CF₃ COOH and refluxed for 1 hour. The reactionmixture is concentrated under reduced pressure and poured intoice-water. The aqueous layer is made alkaline with c.NH₄ OH andextracted with CH₂ Cl₂ /MeOH (4/1). The organic layer is dried andevaporated to prepare 1.701 g (Yield: 57.2%) of the compound (V-6) assolid, which is recrystallized from MeOH-n-hexane to prepare thecompound (V-6) as pale orange plates. mp. 208.0°-209.0° C.

Anal Calcd. (%) for C₁₄ H₁₈ ClNO: C, 66.79; H, 7.21; N, 5.56; Cl, 14.08.Found: C, 66.79; H, 7.26; N, 5.52; Cl, 14.25.

IR(Nujol): 3025, 2773, 2650, 2560, 1607, 1578, 1515, 1453, 1429, 1382.

NMR (CDCl₃ -CD₃ OD) δ:2.66 (quint, J=8 Hz, 2H); 2.47-2.76 (m, 4H); 2.774(t, J=6 Hz, 2H); 3.200 (q, J=2 Hz, 2H); 3.637 (t, J=6 Hz, 2H); 5.972 (s,1H); 6.803, 7.275 (ABq, J=9 Hz, 4H).

(3) A stirred mixture of 1.482 g of the compound (V-6) and 2.57 ml ofmorpholine is refluxed for 2 hr. 15 min. After removal of the reagent,the residue is purified by column chromatography with silica gel,eluting with CH₂ Cl₂ /MeOH/NH₄ OH (128/16/1-64/8/1) to give 1.047 g(Yield: 58.8%) of the compound (Ia-95) as a solid. The maleate isrecrystallized from MeOH-Et₂ O to prepare pale yellow plates. mp.166.0°-167.5° C. (d.)

Anal Calcd. (%) for C₁₈ H₂₆ N₂ O₂. 2C₄ H₄ O₄ : C, 58.22; H, 6.48; N,5.35. Found: C, 58.42; H, 6.41; N, 5.24.

IR (Nujol): 3230, 3063, 2725, 2355, 1715, 1625, 1579, 1519, 1464, 1387.

NMR (CD₃ OD) δ:2.13-2.35 (m, 2H); 2.866 (brs, 2H); 3.03-3.25 (m, 6H);3.25-3.40 (m, 2H); 3.564 (t, J=6 Hz, 3H); 3.883 (t, J=5 Hz, 4H); 3.953(brs, 2H); 5.999 (brs, 1H); 6.264 (s, 4H); 6.778, 7.320 (ABq, J=9 Hz,4H).

EXAMPLE 964-(4-Hydroxyphenyl)-1-(3-(1-pyrrolidinyl)propyl}-1,2,5,6-tetrahydropyridine(Ia-96) ##STR68##

A mixture of 1.50 g of the compound (V-6) and 4.97 ml of pyrrolidine isstirred at room temperature for 18.5 hours and treated in the samemanner as Example 95 (3) to prepare 2.041 g (Yield: 66.1%) of themaleate of the compound (Ia-96) as needles. mp. 145.0°-147.0° C. (dec.).

Anal Calcd. (%) for C₁₈ H₂₆ N₂ O.2C₄ H₄ O₄₄ : C, 60.03; H, 6.42; N,5.50. Found: C, 60.22; H, 6.61; N, 5.40.

IR (Nujol): 3230, 3041, 2710(sh), 2590, 2360, 1709, 1622, 1578, 1518,1461, 1377.

NMR (CD₃ OD) δ:2.00-2.175 (m, 4H); 2.175-2.375 (m, 2H); 2.859 (brs, 2H);3.23-3.48 (m, 8H); 3.542 (t, J=6 Hz, 3H); 3.992 (brs, 2H); 5.995 (brs,1H); 6.257 (s, 4H); 6.778, 7.320 (ABq, J=8 Hz, 4H).

EXAMPLE 971-{3-(N-methylamino)propyl}-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine(Ia-97) ##STR69##

A mixture of 3.00 g of the compound (V-6) and 11.84 ml of BuNH₂ isrefluxed for 5 hours, and treated in the same manner as Example 96 toprepare 2.188 g (Yield: 63.7%) of the compound (Ia-97) as needles. mp.233.0°-236.0° C. (dec.).

IR(Nujol): 3425, 3055, 2778, 2670, 2582, 1665, 1613, 1590, 1515, 1471,1453, 1439, 1428.

NMR (CDCl₃): 0.920 (d, J=7 Hz, 6H); 1.92-2.18 (m, 3H); 2.554 (brs, 2H);2.692 (d, J=7 Hz, 2H); 2.751 (t, J=6 Hz, 2H); 2.854 (t, 2H); 2.854 (t,J=6 Hz, 2H); 3.134 (t, J=6 Hz, 2H); 3.247 (brs, 2H); 5.922 (brs, 1H);6.818, 7.194 (ABq, J=9 Hz, 4H).

EXAMPLE 981-{3-(N-isobutyl-N-methylamino)propyl}-4-(4-hydroxyphenyl)-1,2,5,6-tetrahydropyridine(Ia-98) ##STR70##

Treatment of 2.138 g of the compound (Ia-97) in the same manner asExample 34 prepares 1.528 g (Yield: 70.1%) of the compound (Ia-98) assolid, which is crystallized as maleate and recrystallized from MeOH-Et₂O to prepare pale yellow plates. mp. 150.0°-153.0° C. (dec.).

Anal Calcd. (%) for C₁₉ H₃₀ N₂ O.2C₄ H₄ O₄ : C, 60.38; H, 7.16; N, 5.38.Found: C, 60.66; H, 7.16; N, 5.24.

IR (Nujol): 3235, 2700(sh), 2400, 1618, 1576, 1517, 1459, 1380 (sh),1372(sh), 1359.

NMR (CD₃ OD) δ:1.051 (d, J=7 Hz, 6H); 2.025-2.400 (m, 3H); 2.852 (brs,2H); 2.916 (s, 3H); 3.026 (d, J=7 Hz, 2H); 3.15-3.38 (m, 4H); 3.533 (t,J=6 Hz, 2H); 3.917 (brs, 2H); 5.995 (brs, 1H); 6.257 (s, 4H);6.777,7.318 (ABq, J=9 Hz, 4H).

EXAMPLE 994-(4-Methoxyphenyl)-1-{3-(4-morpholinyl)propyl}-1,2,5,6-tetrahydropyridine(Ia-99) ##STR71##

A stirred mixture of 1.147 g of the compound (IV-8) and 1.76 ml ofmorpholine is refluxed for 1 hour. After removal of the reagent, theresidue is purified by silica gel column chromatography (CH₂ Cl₂/MeOH/NH₄ OH=64/8/1-32/6/1) to prepare 1.34 g of the compound (III-59)as oily substance. The oily product is dissolved in 10 ml of CF₃ COOHand refluxed for 1 hour. After removal of the reagent, the residue ispoured into aq. NH₄ OH and extracted with methylene chloride. Theorganic layer is dried and evaporated under reduced pressure to prepare1.012 g of the oily product. The oily product is subjected to columnchromatography with silica gel, eluting with CH₂ Cl₂ /MeOH(19/1). Theeluate is recrystallized from Et₂ O-n-hexane to prepare of 637 mg(Yield: 50.2%) of the compound (Ia-99) as colorless needles.

mp. 69.0°-70.5° C.

Anal Calcd. (%) for C₁₉ H₂₈ N₂ O₂ : C, 72.12; H, 8.92; N, 8.85. Found:C, 72.01; H, 8.88; N, 9.05.

IR (CHCl₃): 2490, 1610, 1572, 1512, 1466, 1446, 1417, 1402, 1378.

NMR (CHCl₃) δ:1.779 (quint, J=7 Hz, 2H); 2.33-2.63 (m, 10H); 2.706 (t,J=5 Hz, 2H); 3.151 (q, J=4 Hz, 2H); 3.725 (t, J=5 Hz, 4H); 3.802 (s,3H); 5.969 (quint, J=2 Hz, 1H); 6.851, 7.322 (ABq, J=9 Hz, 4H).

EXAMPLE 1004-(4-tert-Butylphenyl)-1-{3-(2,6-dimethylmorpholino)propyl}-1,2,5,6-tetrahydropyridine(Ia-100) ##STR72##

(1) A mixture of 1.150 g of the compound (IV-2) and 2.29 ml of cis2,6-dimethylmorpholine is stirred at 103°-135° C. for 4 hours. Afterremoval of the reagent, the residue is poured into aq.NaOH and extractedwith methylene chloride. The organic layer is dried and evaporated underreduced pressure. The residue is purified by column chromatography withsilica gel, eluting with CH₂ Cl₂ --MeOH (15/1-5/1) to prepare 1.37 g(Yield: 95.0%) of the compound (III-60) as crystals. mp. 137.5°-138.0°C. (dec.)

IR (CHCl₃): 3610, 3010, 2970, 2870, 2820, 1780, 1605, 1512 cm⁻¹.

NMR (CDCl₃) δ:1.161 (d, J=6 Hz, 6H); 1.319 (s, 9H); 1.63-1.88 (m, 7H);2.215 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.30-2.60 (m, 6H); 2.753 (dd, J₁=12 Hz, J₂ =2 Hz, 2H); 2.875 (dd, J₁ =11 Hz, J₂ =2 Hz, 2H); 3.60-3.75(m, 2H); 7.377,7.451 (ABq, J=9 Hz, 4H).

(2) A solution of 1.35 g of the compound (III-60) in 10 ml of CF₃ COOHis refluxed for 4 hour. After removal of the reagent, the residue ispoured into aq.NaHCO₃ and extracted with ethyl acetate. The organiclayer is washed with water, dried and evaporated under reduced pressure.The oily residue is purified by column chromatography with silica gel,eluting with CH₂ Cl₂ /MeOH (25/1-15/1) to prepare 1.29 g (Yield: 86.8%)of the compound (Ia-100) as an oil. The maleate is recrystallized fromMeOH-iPrOH to prepare colorless needles. mp. 192.0°-193.0° C.

Anal Calcd. (%) for C₂₄ H₃₈ N₂ O.2C₄ H₄ O₄ : C, 63.58; H, 7.79; N, 4.64.Found: C, 63.77; H, 7.69; N, 4.65.

IR (Nujol): 1707, 1618 cm⁻¹.

NMR (CDCl₃): 1.260 (d, J=7 Hz, 6H); 1.330 (s, 9H); 2.20-2.40 (m, 2H);2.491 (t, J=12 Hz, 2H); 2.80-2.95 (m, 2H); 3.111 (t, J=8 Hz, 2H);3.28-3.40 (m, 4H); 3.542 (t, J=6 Hz, 2H); 3.80-4.00 (m, 4H); 3.542 (t,J=6 Hz, 2H); 3.80-4.00 (m, 4H); 6.02-6.08 (m, 1H); 6.283 (s, 2H);7.355,7.422 (ABq, J=9 Hz, 4H).

EXAMPLE 101-104

The reaction is performed in the same manner as Example 100 to preparethe compound (Ia). The reaction condition are shown in Tables 13 and 14.

                                      TABLE 13                                    __________________________________________________________________________     ##STR73##                                                                     ##STR74##                                                                    Ex.                    reaction                                                                            purification                                                                            product                                                                             m.p.                             No.                                                                              (IV) (XI)       solvent                                                                           condition                                                                           condition g (Yield)                                                                           (°C.)                                                                      IR                           __________________________________________________________________________    101                                                                              X = Me                                                                             Z = O, R = --  2 hr. CH.sub.2 Cl.sub.2 /MeOH =                                                               III-61                                                                              103.0-                                                                            (CHCl.sub.3)                    3.55 g                                                                             5.77 g         reflux                                                                              15/1-5/1  4.23 g                                                                              104.5                                                                             3600, 3020, 2950, 2920,                                                       2820,                                                               (96.0%)   1513, 1472                   102                                                                              X = Cl                                                                             Z = O, R = H                                                                             --  130-135° C.                                                                  --        III-62                                                                              236.0-                                                                            (Nujol)                         5.1 g                                                                              7.71 g         2.5 hr.         5.97 g                                                                              237.0                                                                             3440, 2930, 2807, 2640,                                                       2550,                                                               (99.5%)   2460                         103                                                                              X = t-Bu                                                                           Z = NH, R = Me                                                                           DMF  95-100° C.                                                                  CH.sub.2 Cl/MeOH/                                                                       III-63                                                                              --  (CHCl.sub.3)                    2.35 g                                                                             1.73 g     20 ml                                                                             2 hr. NH.sub.4 OH =                                                                           1.92 g    3000, 3330, 2960, 2820,                                                       2470,                                                     30/6/1    (65.3%)   1665, 1635, 1605, 1590,                                                       1510                         104                                                                              X = Cl                                                                             Z = NH, R = Me                                                                           DMF  80-85° C.                                                                   CH.sub.2 Cl/MeOH/                                                                       III-64                                                                              --  (CHCl.sub.3)                    2.05 g                                                                             1.62 g     15 ml                                                                             3.5 hr.                                                                             NH.sub.4 OH =                                                                           2.10 g    3590, 3160, 2930, 2810,                                                       2490,                                                     32/6/1    (80.9%)   1677, 1596,                  __________________________________________________________________________                                                     1492                     

                                      TABLE 14                                    __________________________________________________________________________    Ex.           reaction                                                                             purification                                                                            product                                        No.                                                                              (III)                                                                              CF.sub.3 COOH                                                                       condition                                                                            condition g (Yield)                                                                          m.p. (°C.)                                                                   IR                                  __________________________________________________________________________    101                                                                              (III-61)                                                                           45 ml 2.5 hr.                                                                              CH.sub.2 Cl.sub.2 /MeOH =                                                               Ia-101                                                                             186.5-                                                                              (Nujol)                                4.45 g     reflux 15/1-5/1  3.99 g                                                                             188.5*.sup.1                                                                        1709, 1621                                                         (92.0%)                                        102                                                                              (III-62)                                                                           45 ml 7 hr.  CH.sub.2 Cl.sub.2 /MeOH =                                                               Ia-102                                                                             185.5-                                                                              (Nujol)                                3.78 g     reflux 15/1-5/11 3.00 g                                                                             186.5*.sup.1                                                                        2300 (br), 1709, 1622                                              (84.2%)                                        103                                                                              (III-63)                                                                           20 ml room   CH.sub.2 Cl.sub.2 /MeOH/                                                                Ia-103                                                                             235.0-                                                                              (Nujol)                                1.92 g     temperature                                                                          NH.sub.4 OH =                                                                           1.60 g                                                                             250.0*.sup.2                                                                        3440, 3410, 2670, 2580, 2470                      2.5 hr. reflux                                                                       128/16/1  (87.4%)    2420, 1658, 1555, 1507              104                                                                              (III-64)                                                                           25 ml room   CH.sub.2 Cl.sub.2 /MeOH/                                                                Ia-104                                                                             179.0-                                                                              (Nujol)                                2.10 g     temperature                                                                          NH.sub.4 OH =                                                                           1.79 g                                                                             181.0*.sup.2                                                                        3600, 2680, 2530, 2440, 1642                      15 hr. reflux                                                                        128/16/1  (89.6%)    1597, 1496                          __________________________________________________________________________     *.sup.1 maleate                                                               *.sup.2 hydrochloride                                                    

EXAMPLE 1051-[3-{4-(3,4-Dimethoxyphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propylcarbamoyl]-2-oxopyrrolidine(Ia-105) ##STR75##

To a solution of 3.76 g of4-(3,4-dimethoxyphenyl)-1,2,5,6-tetrahydropyridine (V-7), which wasprepared by the reaction of 4-hydroxy-4-(3,4-dimethoxyphenyl)piperidineand p-toluenesulfonic acid, and 2.94 g of1-(3-chloropropylcarbamoyl)-2-oxopyrrolidine in 35 ml of DMF is added3.98 g of K₂ CO₃ and 3.22 g of NaI. The reaction mixture is stirred at100°-105° C. for 6 days under nitrogen gas. After cooling to roomtemperature, the mixture is diluted with ethyl acetate, washed withbrine and dried over MgSO₄. After removal of the solvent, the residue issubjected to column chromatography with silica gel, eluting with CH₂ Cl₂/MeOH (20/1) to prepare 1.78 g (Yield: 33.4%) of the compound (Ia-105)as solid. The oxalate is recrystallized from iPrOH-MeOH to prepareneedles. mp. 178.0°-182.0° C.

Anal Calcd. (%) for C₂₃ H₃₁ N₃ O₈.1/5H₂ O: C, 57.35; H, 6.33; N, 8.67.Found: C, 57.42; H, 6.58; N, 8.73.

IR (Nujol): 3310, 1725(sh), 1708, 1682, 1675, 1600, 1580, 1545, 1545,1520.

NMR (CDCl₃): 1.764 (quint, J=7 Hz, 2H); 1.954 (quint, J=8 Hz, 2H);2.44-2.51 (m, 4H); 2.530 (t, J=8 Hz, 2H); 2.646 (t, J=5 Hz, 2H); 3.094(q, J=3 Hz, 2H); 3.328 (q, J=7 Hz, 2H); 3.795 (t, J=7 Hz, 2H); 3.809,3.827 (sx2, 6H); 5.915 (quint, J=3 Hz, 1H); 6.755 (d, J=9 Hz, 2H);6.84-6.89 (m, 2H); 8.434 (brs, 1H).

EXAMPLE 1061-[3-{4-(4-Methoxyphenyl)-1,2,5,6-tetrahydropyridin-1-yl}propylcarbamoyl]-2-oxopyrrolidine(Ia-106) ##STR76##

The compound (V-8) is reacted in the same manner as Example 105 toprepare the compound (Ia-106). mp. 199.5°-200.0° C. (dec.).

Anal Calcd. (%) for C₂₂ H₂₉ N₃ O₇ : C, 58.81; H, 6.31; N, 9.32. Found:C, 59.02; H, 6.53; N, 9.39.

IR (Nujol): 3300, 2730, 2620, 1700, 1685, 1612, 1548, 1529, 1465.

NMR (CDCl₃): 1.90-2.10 (m, 4H); 2.590 (t, J=7 Hz, 2H); 2.80-2.86 (m,2H); 3.23-3.30 (m, 2H); 3.33-3.52 (m, 4H); 3.778 (s, 3H); 3.898 (m, 2H);5.995 (s, 1H); 6.893, 7.379 (ABq, J=8 Hz, 4H).

EXAMPLE 1071-[4-(4-Tolyl)-1,2,5,6-tetrahydropyridin-1-ylbutylcarbamoyl]-2-oxopyrrolidine(Ia-107) ##STR77##

(1) To a solution of 4.00 g of the compound (II-8) and 4.675 g ofN-Boc-β-alanine in 90 ml of THF are added 5.178 g of1,3-dicyclohexylcarbodiimide and 848 mg of 1-hydroxybenzotriazolehydrate. The reaction mixture is stirred at room temperature for 2 hoursand 10 minutes. After removal of precipitates, the reaction mixture isconcentrated under reduced pressure. The residue is poured into d.HCland extracted with CH₂ Cl₂. The organic layer is washed with aq.NaHCO₃and water in order, dried over MgSO₄ and evaporated under reducedpressure. The residue is subjected to column chromatography with silicagel, eluting with toluene/acetone (3/1-2/1) to prepare 6.862 g ofcrystalline residue. It is recrystallized from methylenechloride-ether-n-hexane to prepare 6.674 g (Yield: 84.8%) of thecompound (IV-9) as colorless needles. mp. 161.5°-163.0° C.

Anal calcd. (%) for C₂₁ H₃₂ N₂ O₄ : C, 67.18; H, 8.46; N, 7.50. Found:C, 66.99; H, 8.57; N, 7.44.

IR (CHCl₃): 3597, 3457, 1709, 1628, 1508, 1474, 1448, 1393, 1369.

NMR (CDCl₃) δ:1.432 (s, 9H); 1.75,2.05 (m, 8H); 2.344 (s, 3H); 2.147 (t,J=7 Hz. 2H); 3.04,3.20 (m, 3H); 3.560 (td, J₁ =12 Hz, J₂ =4 Hz, 1H);3.737 (d, J=14 Hz, 1H); 4.548 (d, J=13 Hz, 1H); 4.833 (brs, 1H);7.177,7.353 (ABq, J=8 Hz, 4H).

(2) A solution of 6.654 g of the compound (IV-9) in 13 ml of CF₃ COOH isstirred at room temperature for 2.5 hours. After removal of the excessreagent, 6.36 g of the crystalline residue is obtained. The residue isrecrystallized from MeOH-Et₂ O to prepare 5.798 g of colorless plates.Then to a solution of 4.818 g of the plates in 30 ml of methanol isadded 5 ml of triethylamine. After removal of the solvent to dryness,the resulting solid is dropwise added to a stirred suspension of 737 mgof LiAlH₄ in 80 ml of THF at room temperature and stirred at the sametemperature for 2.5 hours. After decomposition of the excess reagent bycareful addition of water, the resulting precipitate is filtered off.The organic layer is evaporated to dryness to prepare 3.612 g of theyellow oily residue. The residue is subjected to column chromatographywith silica gel, eluting with CHCl₃ /MeOH/c.NH₄ OH (32/4/0.5-32/6/1) toprepare 1.341 g (Yield: 42.4%) of the compound (V-9).

(3) A mixture of 1.341 g of the compound (V-9) and 1.126 g of1-phenoxycarbonyl-2-oxopyrrolidine is heated at 115° C. for 1 hour 43minutes. The reaction mixture is purified by column chromatography withsilica gel, eluting with toluene/acetone (2/1-1/1) followed byrecrystallization from Et₂ O-n-hexane to prepare 540 mg (Yield: 24.7%)of the compound (Ia-107) as prisms.

mp. 104.0°-104.5° C.

Anal Calcd. (%) for C₂₁ H₂₉ N₃ O₂ : C, 71.05; H, 8.22; N, 11.84. Found:C, 70.95; H, 8.22; N, 11.82.

IR (CHCl₃): 3325, 1714, 1682, 1602, 1548, 1516, 1490, 1461, 1442, 1387.

NMR (CDCl₃) δ:1.62,1.66 (m, 4H); 2.025 (quint, J=7 Hz, 2H); 2.330 (s,3H); 2.30-2.73 (m, 8H); 3.145 (q, J=3 Hz, 2H); 3.338 (q, J=6 Hz, 2H);3.858 (t, J=7 Hz, 2H); 6.016 (quint, J=2 Hz, 1H); 7.117, 7.283 (ABq, J=8Hz, 4H); 8.430 (brs, 1H).

EXAMPLE 1081-[{5-(4-Tolyl)-1,2,5,6-tetrahydropyridin-1-yl}pentylcarbamoyl]-2-oxopyrroridine(Ia-108) ##STR78##

A mixture of 4.675 g of BocNH(CH₂)₄ COOH and 4.00 g of the compound(II-8) is treated in the same manner as Example 107 (1)-(3) to prepare392 mg (Yield: 15.0%) of the compound (Ia-108). mp.58.5°-59.5° C.

Anal Calcd. (%) for C₂₂ H₃₁ N₃ O₂ : C, 71.23; H, 8.42; N, 11.46. Found:C, 71.51; H, 8.46; N, 11.37.

IR (CHCl₃): 3321, 1714, 1681, 1548, 1516, 1489, 1461, 1387.

NMR (CDCl₃ -CD₃ OD) δ:1.32-1.45 (m, 2H); 1.52-1.70 (m, 4H); 2.039(quint, J=7 Hz, 2H); 2.333 (s, 3H); 2.429-2.507 (m, 2H); 2.615 (t, J=8Hz, 4H); 2.723 (t, J=6 Hz, 2H); 3.161 (q, J=3 Hz, 2H); 3.303 (q, J=6 Hz,2H); 3.854 (t, J=7 Hz, 2H); 6.032 (s, 1H); 7.126, 7.292 (ABq, J=8 Hz,4H); 8.460 (brs, 1H).

EXAMPLE 1091-{3-(3,4-Dichlorophenoxy)propyl}-4-(4-hydroxyphenyl)1,2,5,6-tetrahydropyridine(Ia-109) ##STR79##

(1) A mixture of 3.6 g of 3-(3,4-dichlorophenoxy)propylchloride, whichwas prepared by the reaction of 3,4-dichlorophenol with3-bromopropylchloride, and 3.12 g of4-hydroxy-4-(4-methoxyphenyl)piperidine, 4.15 g of K₂ CO₃, and 3.37 g ofNaI in 35 ml of DMF is stirred at 105° C. for 10 hour. The reactionmixture is poured into ice-water, and the resulting precipitates areextracted with methylene chloride. The organic layer is dried andevaporated under reduced pressure. The residue is purified by columnchromatography with silica gel, eluting with CH₂ Cl₂ /MeOH (20/1-10/1)followed by recrystallization from methylene chloride to prepare 5.86 g(Yield: 95.2%) of the compound (III-65) as colorless needles. mp.131.0°-132.0° C.

Anal Calcd. (%) for C₂₁ H₂₅ N₂ O₃ Cl₂ : C, 61.39; H, 6.20; N, 3.55; Cl,17.28. Found: C, 61.47; H, 6.14; N, 3.41; Cl, 17.30.

IR (CHCl₃): 3600, 1612, 1595, 1568, 1513, 1480(sh), 1468.

NMR (CDCl₃) δ:1.563 (s, 1H); 1.772 (dd, J₁ =14 Hz, J₂ =3 Hz, 2H); 1.999(quint, J=6 Hz, 2H); 2.137 (td, J₁ =13 Hz, J₂ =4 Hz, 2H); 2.478 (td, J₁=12 Hz, J₂ =2 Hz, 2H); 2.575 (t, J=7 Hz, 2H); 2.811 (J₁ =11 Hz, J₂ =3Hz, 2H); 3.803 (s, 3H); 4.004 (t, J=6 Hz, 2H); 6.760 (dd, J₁ =9 Hz, J₂=3 Hz, 1H); 6.887 (d, J=9 Hz, 2H); 7.013 (d, J=3 Hz, 1H); 7.308 (d, J=9Hz, 1H); 7.438 (d, J=9 Hz, 2H).

(2) To a stirred solution of 2.08 g of the compound (III-65) in 50 ml ofmethylene chloride is added 1.44 ml of BBr₃ under ice-cooling. Afterremoval of the reagent, the residue is poured into aq.NaHCO₃ andextracted with ethyl acetate. The organic layer is washed with water,dried and evaporated under reduced pressure. The resulting oily residue1.91 g is dissolved in 20 ml of CF₃ COOH and refluxed for 2 hour. Afterremoval of the reagent, the residue is poured into aq.NaHCO₃ andextracted with ethylacetate. The organic layer is washed, dried andevaporated. The residue is purified by column chromatography with silicagel(toluene/ethyl acetate(1/1)-CH₂ Cl₂ /MeOH (20/1)) to prepare 270 mg(Yield: 33%) of the compound (Ia-109) as a solid. The maleate isrecrystallized from MeOH-iPrOH to prepare needles. mp. 167.0°-168.0° C.(dec.).

Anal Calcd. (%) for C₂₀ H₂₁ NO₂ Cl₂ : C,58.08; H,5.05; N,2.93; Cl,14.55.Found: C,58.31; H,5.10; N,2.83; Cl,14.34.

EXAMPLE 1101-{3-(3,4-Dichlorophenoxy)propyl}-4-(3,4-dichlorophenyl)1,2,5,6-tetrahydropyridine(Ia-110) ##STR80##

(1) 3-(3,4-dichlorophenoxy)propylchloride 1.38 g and4-hydroxy-4-(3,4-dichlorophenyl)piperidine 1.35 g are reacted in thesame manner as Example 109 (1) to prepare 2.40 g (Yield: 97.5%) of1-{3-(3,4-dichlorophenoxy)propyl}-4-hydroxy-4-(3,4-dichlorophenyl)piperidine (III-66). mp.118.0°-118.5° C.

(2) A solution of 1.61 g of the compound (III-66) in 20 ml oftrifluoroacetic acid is refluxed for 3.5 hours. After removal of thereagent, the residue is poured into aq.NaHCO₃ and extracted withmethylene chloride. The organic layer is washed, dried and evaporated.The residue is purified by column chromatography with silica gel,eluting with CH₂ Cl₂ /MeOH(25/1) to prepare 1.45 g (Yield: 94.0%) of thecompound (Ia-110) as oxalate. The oxalate is recrystallized fromMeOH-iPrOH to prepare the compound (Ia-110) as needles. mp.163.5°-165.0° C. (dec.).

Anal Calcd. (%) for C₂₀ H₁₉ NO₂ Cl₄ : C, 50.43; H, 4.09; N, 2.72; Cl,27.15. Found: C, 50.70; H, 4.06; N, 2.69; Cl, 27.21.

IR (Nujol): 2930, 1713, 1695(sh), 1615, 1597, 1563.

NMR (CDCl₃): 2.045 (quint, J=7 Hz, 2H); 2.657 (t, J=8 Hz, 2H); 2.554 (m,2H); 2.745 (t, J=5 Hz, 2H); 3.202 (q, J=3 Hz, 2H); 4.026 (t, J=6 Hz,2H); 6.110 (m, 1H); 6.766 (dd, J₁ =19 Hz, J₂ =3 Hz, 1H); 7.015 (d, J=3Hz, 1H); 7.19-7.47 (m, 4H).

EXAMPLE 1111-{3-(3,4-Dichlorophenoxy)propyl}-4-(4-trifluoromethylphenyl)-1,2,5,6-tetrahydropyridine(Ia-111) ##STR81##

(1) 3-(3,4-dichlorophenoxy)propylchloride 2.00 g and4-hydroxy-4-(4-trifluoromethylphenyl)piperidine 1.95 g are reacted inthe same manner as Example 109 (1) to prepare 3.16 g (Yield: 88.7%) ofthe compound (III-67). mp. 196.0°-196.5° C.

(2) A solution of 2.65 g of the compound (III-67) in 30 ml oftrifluoroacetic acid is refluxed for 41 hours. After removal of thereagent, the residue is poured into aq.NaHCO₃ and extracted with ethylacetate. The organic layer is dried and evaporated. The residue ispurified by column chromatography with silica gel (toluene/ethyl acetate(3/1), CH₂ Cl₂ /MeOH(25/1)) to prepare 1.65 g (Yield: 65.9%) of thecompound (Ia-111) as a solid, which is recrystallized from Et₂ O toprepare colorless needles, mp.83.5°-84.0° C. The oxalate melts at mp.195.5°-196.0° C.

Anal Calcd. (%) for C₂₁ H₂₀ NO₂ Cl₂ F₃.C₂ H₂ O₄ : C, 52.93; H, 4.33; N,2.71; Cl, 13.42; F, 11.08. Found: C, 53.09; H, 4.26; N, 2.69; Cl, 13.65;F, 10.95.

IR (CHCl₃): 2950, 2930, 2830, 2790, 1618, 1597, 1469.

NMR (CDCl₃): 2.052 (quint, J=7 Hz, 2H); 2.52-2.65 (m, 2H); 2.661 (t, J=7Hz, 2H); 2.759 (t,J=6 Hz, 2H); 3.222 (q, J=3 Hz, 2H); 6.171 (m, 1H);6.765 (dd, J₁ =9 Hz, J₂ =3 Hz, 1H); 7.015 (d, J=3 Hz, 1H); 7.312 (d, J=9Hz, 1H); 7.479, 7.574 (ABq, J=8 Hz, 4H).

REFERENCE EXAMPLE 1 4-Hydroxy-4-(3,4-dichlorophenyl)piperidine (II-1)##STR82##

A mixture of 64.2 g of1-ethoxycarbonyl-4-hydroxy-4-(3,4-dichlorophenyl)piperidine (X-1) and asolution of 72.4 g of KOH in 700 ml of nBuOH is refluxed for 2 hours andevaporated. The reaction mixture is concentrated under reduced pressureand extracted with ethyl acetate. The organic layer is washed withwater, dried and evaporated. The resulting crystalline residue isrecrystallized from ethyl acetate to prepare 44.7 g (Yield: 90.0%) ofthe compound (II-1). mp. 144.5°-146.0° C.

Anal Calcd. (%) for C₁₄ H₁₇ NO₃ Cl₂ : C, 53.62; H, 5.26; N, 5.68; Cl,28.98. Found: C, 53.68; H, 5.32; N, 5.69; Cl, 28.81.

IR (Nujol): 3320, 3100, 1438.

NMR (CD₃ OD) δ:1.651 (dd, J₁ =12 Hz, J₂ =2 Hz, 2H); 1.936 (td, J₁ =12Hz, J₂ =5 Hz, 2H); 1.651 (dd, J₁ =12 Hz, J₂ =2 Hz, 2H); 3.074 (td, J₁=12 Hz, J₂ =3 Hz, 2H); 7.402 (dd, J₁ =8 Hz, J₂ =2 Hz, 1H); 7.480 (d, J=8Hz, 1H); 7.662 (d, J=2 Hz, 1H).

REFERENCE EXAMPLE 2-19

The reaction is performed in the same manner as Reference Example 1 toprepare the compound (II). The reaction conditions and physicalconstants are shown in Tables 15 and 16.

                                      TABLE 15                                    __________________________________________________________________________     ##STR83##                                                                           (X)                    (II) g (Yield)                                  Ref. Ex. No.                                                                         X =  Base solvent                                                                              reflux time                                                                         m.p. (°C.)                                                                     IR                                      __________________________________________________________________________    2      CF.sub.3 (p)                                                                       KOH  EtOH   5 hours                                                                             (II-2)                                                 27.3 g                                                                             (28.07 g)                                                                          (450 ml)     13.24 g (63.0%)                                        (X-2)                                                                  3      n-Pr (p)                                                                           KOH  n-BuOH 5.5 hours                                                                           (II-3)                                                 44.0 g                                                                             (49.3 g)                                                                           (640 ml)     30.47 g (92.0%)                                        (X-3)                                                                  4      Et (p)                                                                             KOH  n-BuOH 2 days                                                                              (II-4)                                                 22.42 g                                                                            (26.37 g)                                                                          (500 ml)     13.88 g (83.7%)                                        (X-4)                                                                  5      Ph (p)                                                                             KOH  n-BuOH 15 hours                                                                            (II-5)                                                 18.65 g                                                                            (18.70 g)                                                                          (500 ml)     13.44 g (92.6%)                                        (X-5)                                                                  6      t-Bu (p)                                                                           KOH  n-BuOH 5.5 hours                                                                           (II-6)                                                 46.67 g                                                                            (50.9 g)                                                                           (700 ml)     33.64 g (92.0%)                                        (X-6)                                                                  7      CH.sub.3 (p)                                                                       KOH  BuOH   3.5 hours                                                                           (II-8)  (Nujol)                                        49.86 g                                                                            (61.8 g)                                                                           (700 ml)     33.20 g (92.0%)                                                                       3310, 1598, 1502, 1490                         (X-7)                  135.5-137.5                                                                           1445                                    8      CH.sub.3 (m)                                                                       KOH  EtOH   6 days                                                                              (II-9)  (Nujol)                                        21.2 g                                                                             (26.3 g)                                                                           (450 ml)     10.25 g (66.6%)                                                                       3440, 3280, 3220, 3179                         (X-8)                  154.5-155.5                                                                           1606, 1590, 1490, 1475                  9      CH.sub.3 (o)                                                                       KOH  EtOH   5 days                                                                              (II-10) (Nujol)                                        14.7 g                                                                             (18.21 g)                                                                          (350 ml)     7.90 g (74.0%)                                                                        3440, 3280, 3220, 3170                         (X-9)                  141.0-142.0                                                                           1608, 1590, 1490                        10     3,4-diMe                                                                           KOH  EtOH   10 days                                                                             (II-11) (Nujol)                                        20.2 g                                                                             (23.76 g)                                                                          (500 ml)     13.97 g (93.5%)                                                                       3590, 3380, 1600, 1502                         (X-10)                 --      1467, 1448                              11     3,5-diMe                                                                           KOH  EtOH   12 days                                                                             (II-12) (Nujol)                                        22.7 g                                                                             (26.7 g)                                                                           (650 ml)     14.85 g (88.4%)                                                                       3280, 3120(br), 1605                           (X-11)                 182.0-183.0                                                                           1415                                    12     Cl (m)                                                                             KOH  EtOH   2 days                                                                              (II-13) (Nujol)                                        22.2 g                                                                             (25.5 g)                                                                           (350 ml)     13.68 g (82.6%)                                                                       3220, 3080, 1595, 1570                         (X-12)                 100.0-101.0                                                                           1432, 1408                              13     Cl (o)                                                                             NaOH THF/H.sub.2 O                                                                        5 days                                                                              (II-14) (KBr)                                          9.2 g                                                                              (3.89 g)                                                                           (10 ml/20 ml)                                                                              4.95 g (72.0%)                                                                        3440, 3280, 3060, 1475                         (X-13)                 166.5-167.5                                                                           1442, 1430                              14     3,5-diCl                                                                           KOH  EtOH   11 days                                                                             (II-15) (Nujol)                                        25.11 g                                                                            (25.74 g)                                                                          (550 ml)     15.5 g (79.8%)                                                                        3310, 3100, 3080, 1591                         (X-14)                 213.0-214.0                                                                           1568, 1450, 1425, 1410                  15     Br (p)                                                                             KOH  EtOH   10 days                                                                             (II-16) (Nujol)                                        21.0 g                                                                             (20.87 g)                                                                          (500 ml)     9.23 g (56.3%)                                                                        3280, 3050, 1588, 1492                         (X-15)                 159.5˜161.5                                                                     1478, 1420                              16     F (p)                                                                              KOH  Dioxane/H.sub.2 O                                                                    6 days                                                                              (II-17) (Nujol)                                        23.2 g                                                                             (17.36 g)                                                                          (170/70 ml)  9.82 g (58.8%)                                                                        3280, 3130, 1602, 1512                         (X-16)                 --      1455                                    17     CF.sub.3 (m)           (II-18) (CHCl.sub.3)                                   Cl (p)                                                                             KOH  nBuOH  2 hours                                                                             22.30 g (67.0%)                                                                       3595, 2950, 2850, 1607                         41.8 g                                                                             (42.7 g)                                                                           (580 ml)     135.0-136.5                                                                           1576, 1483                                     (X-17)                                                                 18     *.sup.1                                                                            KOH  EtOH   2 days                                                                              (II-19) (Nujol)                                        (X-18)                                                                             (18.30 g)                                                                          (350 ml)     11.88 g 3290, 1540, 1417                               27.1 g                 149.5- 150.0                                    19     *.sup.2                                                                            KOH  nBuOH  2 days                                                                              (II-20) (Nujol)                                        (X-19)                                                                             (19.82 g)                                                                          (500 ml)     9.51 g (62.1%)                                                                        3280, 1640, 1540                               19.7 g                 151.0-152.5                                     __________________________________________________________________________     ##STR84##                                                                     ##STR85##                                                                

                                      TABLE 16                                    __________________________________________________________________________    Compd.                                                                             m.p. (°C.)                                                                   Anal Calcd. (%)                                                    No.  (solvent*)                                                                          Found (%) IR (cm.sup.-1)                                                                        NMR (δ)                                    __________________________________________________________________________    II-2 136.0-137.0                                                                         C.sub.12 H.sub.14 NOF.sub.3 :                                                           (Nujol) (CD.sub.3 OD)                                         (ethyl                                                                              C, 58.83(58.77)                                                                         3290, 1619, 1443                                                                      1.680(d-d, J.sub.1 =14Hz, J.sub.2 =2Hz,                                       2H):2.004(t-d, J.sub.1 =14Hz, J.sub.2 =5Hz,                                   2H):                                                  acetate)                                                                            H, 5.74(5.75)                                                                           1439, 1422, 1410                                                                      2.866(d-d, J.sub.1 =13Hz, J.sub.2 =2Hz,                                       2H):3.107(t-d, J.sub.1 =13Hz, J.sub.2 =2Hz,                 N, 5.73(5.71)     2H):7.625(d, J=9Hz, 2H):7.698(d, J=9Hz, 2H)                 F, 23.13(23.24)                                                    II-3 178.5-179.5                                                                         C.sub.14 H.sub.21 NO.C.sub.2 H.sub.2 O.sub.4                                            (CHCl.sub.3)                                                                          (CDCl.sub.3)                                          (oxalate)                                                                           C, 61.77(62.12)                                                                         3600, 3350(br),                                                                       0.933(t, J=7Hz, 3H):1.620(sextet, J=8Hz,                                      2H):1.876(d, J=14Hz,                                  (i-PrOH)                                                                            H, 7.42(7.49)                                                                           1593, 1510, 1468                                                                      2H):2.330(t-d, J.sub.1 =14Hz, J.sub.2 =4Hz,                                   2H):2.564(t, J=7Hz, 2H):3.244                               N, 4.50(4.53)                                                                           1422    (d, J=12Hz, 2H):3.367(t, J=12Hz,                                              2H):7.164(d, J=8Hz, 2H):7.40                                                  (d, J=8Hz, 2H)                                   II-4 119.0-120.0                                                                         C.sub.13 H.sub.14 NO                                                                    (CHCl.sub.3)                                                                          (CD.sub.3 OD)                                         (Et.sub.2 O-                                                                        C, 75.97(76.05)                                                                         3600, 1510, 1469                                                                      1.204(t, J=7Hz, 3H):1.676(d-d, J.sub.1                                        =14Hz, J.sub.2 =2Hz, 2H):1.933                        ethyl H, 9.33(9.33)                                                                           1440, 1420, 1410                                                                      (t-d, J.sub.1 =14Hz, J.sub.2 =5Hz,                                            2H):2.616(q, J=8Hz, 2H):2.852(d-d, J.sub.1                                    =12                                                   acetate)                                                                            N, 6.78(6.82)                                                                           (sh)    Hz, J.sub.2 =3Hz, 2H):3.084(t-d, J.sub.1                                      =12Hz, J.sub.2 =3Hz, 2H):7.156(d, J=8                                         Hz, 2H):7.397(d, J=8Hz, 2H)                      II-5 182.5-184.0                                                                         C.sub.17 H.sub.19 NO.1/6H.sub.2 O                                                       (Nujol) (CDCl.sub.3 --CD.sub.3 OD = 4/1)                      (MeOH--                                                                             C, 79.84(79.65)                                                                         3320, 1595, 1581                                                                      1.804(d, J=12Hz, 2H):2.052(t-d, J.sub.1                                       =14Hz, J.sub.2 =5Hz, 2H):2.096(d-                     CH.sub.2 Cl.sub.2)                                                                  H, 7.48(7.60)                                                                           1563, 1490, 1450                                                                      d, J.sub.1 =13Hz, J.sub.2 =2Hz,                                               2H):3.172(t-d, J.sub.1 =12Hz, J.sub.2 =3Hz,                                   2H):7.29-                                                   N, 5.44(5.46)     7.63(m, 9H)                                      II-6 185.0-186.0                                                                         C.sub.15 H.sub.23 NO.H.sub.2 O                                                          (Nujol) (CD.sub.3 OD)                                         (CHCl.sub.3 --                                                                      C, 71.18(71.67)                                                                         3480(sh), 3390,                                                                       1.301(s, 9H):1.684(d-d, J.sub.1 =14Hz,                                        J.sub.2 =2Hz, 2H):1.839(t-d, J.sub.1 =14              MeOH) H, 9.86(10.02)                                                                          3320, 3290, 3090                                                                      Hz, J.sub.2 =4Hz, 2H):2.857(d-m, J.sub.1                                      =12Hz, 2H):3.086(t-d, J.sub.1 =13Hz, J.sub.2                                  =                                                           N, 5.67(5.57)                                                                           1668, 1508, 1470                                                                      3Hz, 2H):7.360(d, J=9Hz, 2H):7.404(d,            __________________________________________________________________________                                 J=9Hz)                                            *a solvent for recrystallization                                         

EVALUATION OF BIOLOGICAL ACTIVITY Experiment

After the decapitation of rats, the objective tissues were rapidlyremoved and each was weighed. Each tissue was homogenized withtwenty-fold amount of ice-cold 50 mM Tris-HCl buffer (pH7.8),homogenized, and centrifuged at 40,000×g for 10 minutes. The supernatantwas removed and pellets were then resuspended in the buffer andrecentrifuged. The procedure is repeated 3 times. Then these obtainedsamples were freeze-dried in liquid nitrogen and preserved at -80° C. Onthe test day, the sample was thawed at room temperature and centrifugedat 40,000×g for 10 minutes, the pellets were then suspended in anincubation buffer and used as the receptor preparation. The preparationwas added to the mixture containing the labelled ligand and the testdrug, and filtered through Whatman GF/C filters and washed to terminatethe on reaction. Radioactivity on the filters was determined by a liquidscintillation counter and Ki value was calculated.

1. σ receptor

Sigma receptor binding was initiated by the addition of the receptorpreparation (cortex tissue, 0.7 mg protein/ml) to a mixture containing 5nM of [³ H]3PPP [3-hydroxyphenyl-N-(1-propyl)piperidine] and the testcompound dissolved in 50 mM Tris-HCl buffer (pH 7.8). Incubation wascarried out at 25° C. for 90 minutes. Specific sigma receptor bindingwas defined as the difference in amount of [³ H]3PPP bound to the tissuein the presence or the absence of 10 μM haloperidol.

2. DA2 receptor

DA2 receptor binding was initiated by the addition of the receptorpreparation (striatal tissue, 0.3 mg protein/ml) to a mixture containing0.2 nM of [³ H]spiroperidol and the test compound dissolved in 50 mMTris-HCl buffer containing 100 mM-NaCl and 5 mM-KCl (pH 7.4). Incubationwas carried out at 37° C. for 10 minutes. Specific DA2 receptor bindingwas defined as the difference in amount of [³ H]spiroperidol bound tothe tissue in the presence or the absence of 10 μM haloperidol.

3. 5HT2 receptor

5HT2 receptor binding was initiated by the addition of the receptorpreparation (cortex tissue, 0.5 mg protein/ml) to a mixture containing 1nM of [³ H]spiroperidol and the test compound dissolved in 50 mMTris-HCl buffer (pH 7.4). Incubation was carried out at 37° C. for 15minutes. Specific 5HT2 receptor binding was defined as the difference inamount of [³ H]spiroperidol bound to the tissue in the presence or theabsence of 1 mM serotonin.

4. PCP receptor

PCP receptor binding was initiated by the addition of the receptorpreparation (cortex tissue, 0.2 mg protein/ml) to a mixture containing 5nM of [³ H]TCP and the test compound dissolved in 5 mM Tris-HCl buffer(pH 7.8). Incubation was carried out at 25° C. for 30 minutes. SpecificPCP receptor binding was defined as the difference in amount of [³ H]TCPbound to the tissue in the presence or the absence of 10 μM PCP.

The test results are shown in Table 17.

                  TABLE 17                                                        ______________________________________                                        Test      Ki (μM)                                                          compound   PCP    σ      DA2  5-HT2                                     ______________________________________                                        Ia-2       31     0.0041       4.7  0.55                                      Ia-3       16     0.0095       4.0  1.70                                      Ia-6       49     0.0027       2.2  2.50                                      Ia-8       >62    0.0013       1.20 2.90                                      Ia-9       33     0.0061       1.60 1.20                                      Ia-11      23     0.0026       4.50 4.40                                      Ia-13      26     0.0022       0.32 0.77                                      Ia-24      32     0.0058       1.10 0.38                                      Ia-30      >63    0.0013       2.00 3.70                                      Ia-35      18     0.0018       4.60 3.20                                      Ia-56      44     0.0065       4.50 8.90                                      Ia-57      44     0.0063       2.40 0.14                                      Ia-94      27     0.0013       1.40 1.90                                      Ia-101     >63     0.00031     1.80 7.70                                      Ia-102     >71     0.00071     3.20 5.70                                      Ia-111     >63    0.0029       0.63 0.39                                      Ia-112     >63    0.0025       >21  2.60                                      ______________________________________                                    

From the above, the compound of the present invention has low affinityto DA2 receptor and high affinity to σ receptor, and has useful activityas psychotropic agents.

What we claim is:
 1. A compound of the formula: ##STR86## wherein Ar isphenyl which has identically or differently one or two substituentsselected from the group consisting of lower alkyl, lower alkoxy,trifluoromethyl, hydroxy and phenyl, which latter phenyl may besubstituted by hydroxy, lower alkyl, lower alkoxy or halogen, or Ar isphenyl which is substituted by two halogen atoms;n is an integer of from2 to 6; R¹ is hydrogen or lower alkyl; the group ##STR87## may haveidentically or differently 1 to 3 substituents selected from the groupconsisting of lower alkyl, halogen, oxo and phenyl, which phenyl may besubstituted by hydroxy, lower alkyl, lower alkoxy or halogen; and p andq each is an integer of 0 to 1, excluding the case where p is 0 when qis 1; or a pharmaceutically acceptable acid addition salt thereof.
 2. Acompound of the formula: ##STR88## wherein n is an integer of from 2 to6; p and q each is an integer of 0 or 1, excluding the case where p is 0when q is 1; or a pharmaceutically acceptable acid addition saltthereof.
 3. A compound of the formula: ##STR89## wherein n is an integerof from 2 to 6; p and q each is an integer of 0 or 1, excluding the casewhere p is 0 when q is 1; or a pharmaceutically acceptable acid additionsalt thereof.
 4. A compound of the formula: ##STR90## wherein R¹ ishydrogen or lower alkyl; n is an integer of from 2 to 6; p and q each isan integer of 0 or 1, excluding the case where p is 0 when q is 1; or apharmaceutically acceptable acid addition salt thereof.